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Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment

Ola Habanjar, Rea Bingula, Caroline Decombat and 3 more

International Journal of Molecular Sciences · 2023 · Review · CC BY

doi:10.3390/ijms24044002

Abstract

Several immune and immunocompetent cells, including dendritic cells, macrophages, adipocytes, natural killer cells, T cells, and B cells, are significantly correlated with the complex discipline of oncology. Cytotoxic innate and adaptive immune cells can block tumor proliferation, and others can prevent the immune system from rejecting malignant cells and provide a favorable environment for tumor progression. These cells communicate with the microenvironment through cytokines, a chemical messenger, in an endocrine, paracrine, or autocrine manner. These cytokines play an important role in health and disease, particularly in host immune responses to infection and inflammation. They include chemokines, interleukins (ILs), adipokines, interferons, colony-stimulating factors (CSFs), and tumor necrosis factor (TNF), which are produced by a wide range of cells, including immune cells, such as macrophages, B-cells, T-cells, and mast cells, as well as endothelial cells, fibroblasts, a variety of stromal cells, and some cancer cells. Cytokines play a crucial role in cancer and cancer-related inflammation, with direct and indirect effects on tumor antagonistic or tumor promoting functions. They have been extensively researched as immunostimulatory mediators to promote the generation, migration and recruitment of immune cells that contribute to an effective antitumor immune response or pro-tumor microenvironment. Thus, in many cancers such as breast cancer, cytokines including leptin, IL-1B, IL-6, IL-8, IL-23, IL-17, and IL-10 stimulate while others including IL-2, IL-12, and IFN-γ, inhibit cancer proliferation and/or invasion and enhance the body’s anti-tumor defense. Indeed, the multifactorial functions of cytokines in tumorigenesis will advance our understanding of cytokine crosstalk pathways in the tumor microenvironment, such as JAK/STAT, PI3K, AKT, Rac, MAPK, NF-κB, JunB, cFos, and mTOR, which are involved in angiogenesis, cancer proliferation and metastasis. Accordingly, targeting and blocking tumor-promoting cytokines or activating and amplifying tumor-inhibiting cytokines are considered cancer-directed therapies. Here, we focus on the role of the inflammatory cytokine system in pro- and anti-tumor immune responses, discuss cytokine pathways involved in immune responses to cancer and some anti-cancer therapeutic applications.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Immunology is closely related to the complex discipline of oncology, where the immune response is recognized as a double-edged sword in terms of tumor progression, either by attenuating or promoting cancer invasiveness and metastasis. There are two distinct aspects of the immune response: (1) the innate, mediated by non-specific immunity cells, such as neutrophils, monocytes, macrophages, dendritic cells (DCs), natural killer (NK) cells, and γδT lymphocytes; and (2) the adaptive, mediated by specific immunity cells, such as T (CD4+ helpers and CD8+ cytotoxic) and B lymphocytes, both working together to protect against pathogens and abnormal cells. Immunocompetent cells (cells capable of mediating an effective immune response) include non-specific and specific immunity cells, but also non-immune cells, such as adipocytes. The latter can act as antigen-presenting cells (APCs) since they can express major histocompatibility complex (MHC) class I and II molecules and present their antigenic determinants to T cells to trigger an immune response, cytokine production, and subsequent intercellular signaling. In obese individuals, adipocytes can recruit and activate immune cells, such as adipose-resident T cells (ARTs) to stimulate the adipose pro-inflammatory response during the progression of obesity. Naïve CD4+ T helper cells (Th) are activated after interaction with the antigen-MHC complex and differentiated into subsets of helper T cells, such as Th1, Th2, Th17, and regulatory T cell (Tregs) that produce different combinations of cytokines and other factors. Tregs are identified as those suppressing anti-tumor activity by inhibiting, among others, the differentiation of naïve CD4+ T cells into Th1, thus enhancing the tumor development and metastasis. In addition, some immune cells play a dual role, such as neutrophils (cancer promoting—tumor-associated neutrophils (TANs)/suppressing) and macrophages, divided into M1-like macrophages (pro-inflammatory and anti-cancer activities), M2-like macrophages (anti-inflammatory and pro-cancer activities) and tumor-associated macrophages (TAMs).

These immune cells send signals to communicate with the microenvironment using cytokines that act as chemical messengers in an endocrine, paracrine, or autocrine manner and mediate intercellular communication of the immune system. Cytokines, called immunomodulatory agents, are synthesized under physiological and pathological conditions, and secreted by different cell types, such as immune cells, immunocompetent cells (e.g., adipocytes), and some cancer cells. They are involved in cellular (type 1) and antibody-mediated (type 2) immunity, as anti/pro-inflammatory and pro/anti-tumorigenic effectors depending on the microenvironment. Cytokines can affect the actions of other cells by binding to their surface receptors and subsequently activating numerous signaling pathways. There are different types of cytokines, including chemokines, interleukins, adipokines, transforming growth factors (TGFs), tumor necrosis factor (TNF), colony-stimulating factors (CSFs) and interferons (IFN), which can act alone, in synergic, protagonist, or antagonist manner to regulate inflammatory and immune responses.

Chemokines are chemoattractant cytokines that give chemical orders to attract inflammatory cells, such as leukocytes (monocytes, neutrophils) as well as other cell types, including endothelial and epithelial cells, to the site of interest. They are classified as CX3C, CXC, CC, or C chemokines based on the positioning of conserved cysteine residues and interact with G protein-linked transmembrane receptors called chemokine receptors. Depending on their function, chemokines can be inflammatory (e.g., CXCL8, CCL3), recruiting cells through inflammatory stimulus, or/and homeostatic (movement and localization of cell subsets).

Moreover, interleukins (ILs), low molecular weight cytokines, have both pro- and anti-inflammatory properties. They are secreted by almost all immunocompetent cells, such as (but not limited to) T cells, granulocytes, monocytes, macrophages, adipocytes, and endothelial cells. They play essential roles in the development, differentiation, activation, maturation, migration, and adhesion of immune cells.

Adipokines, or adipocytokines, are cytokines specifically secreted by adipose tissue that is composed mainly of adipocytes, pre-adipocytes, macrophages, stromal cells, fibroblasts, and endothelial cells. They include adipose tissue-specific cytokines (adiponectin, leptin), but also other cytokine types, such as interleukins, TNFs, or chemokines. Adipokines regulate energy expenditure, inflammation, appetite control, and fat distribution, but can contribute to an obesity-related low-grade inflammation, development of metabolic diseases, and also to cancer progression and metastasis. There are two groups of adipokines based on their effect on the immune system: pro-inflammatory, such as leptin, TNFα, interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8), potentially linking adiposity and inflammation, and anti-inflammatory, such as interleukin-10 (IL-10) and adiponectin. Some of the adipokines participate in the anti-cancer activity, such as adiponectin and some present tumorigenic properties, such as leptin.

TGFs are a subgroup of a larger family of protein hormones that are up-regulated in some human cancers and play several roles in growth and development of non-malignant and malignant cells. TGFα belongs to the epidermal growth factor (EGF) family, can induce epithelial development, cell proliferation, and is involved in tumorigenesis and angiogenesis. It is secreted by M2 macrophages and various tumor cells, and can regulate T cells, NK cells, and macrophages in tumor microenvironment (TME), which contributes to the suppression of anti-tumor immunity and promotes tumor growth.

CSF has been implicated, for example, in breast carcinogenesis (varies by menopausal status). TNFα is a key cytokine involved in the generation of the proinflammatory response and many different cellular responses, such as the up-regulation of anti-apoptotic genes, inducing cell survival and proliferation, but also cancer invasion. As an adipokine, it has an impact on the endocrine functions of adipose tissue and is associated with obesity, promotes insulin resistance and type 2 diabetes.

Finally, IFN, named after its ability to interfere with viral growth, is released by host cells and plays a controversial role in immune status modulation, anti-microbial/anti-viral host defense, up-regulation of antigen presentation and expression of MHC antigens. Type I IFNs (IFN-α, IFN-β) are produced by fibroblasts and monocytes when the body recognizes a virus that has invaded it. They stimulate the expression of proteins that will prevent the virus from producing and replicating its RNA and/or DNA. Type II IFN (IFN-γ) is released by CD8+ T and Th1 cells, activating cells, such as NK cells, M1-type macrophages and cytotoxic CD8+ T cells, increasing MHC I and II presentation, thus enhancing anti-tumor immunity.

So, cytokines affect the growth and function of many cell types and can activate or modulate specific or non-specific anti-tumor responses. In breast cancer, cancer cells are directly in contact with the adipose microenvironment and reciprocal interactions with immunocompetent cells, immune cells, infiltrating immune cells (TANs, M2, TAMs), fibroblasts, cancer-associated fibroblasts (CAFs), and endothelial cells, have been revealed, particularly in obese people. The TME could play a critical role in all stages of tumor development, contributing to the development, progression, and metastasis of malignant cells. Some cytokines (leptin, IL-1β, IL-6, IL-8, IL-23, IL-17, TGF-β, IL-10) are mostly reported to stimulate while others (Il-2, IL-12, IFNs) inhibit breast cancer proliferation and/or invasion. The former contribute to the establishment of a tumor-promoting inflammation, recognized as a hallmark of cancer. There are two types of inflammation, acute inflammation induced by common bacterial infections and viruses, and chronic inflammation associated with chronic disease, obesity, and cancer. To some extent, inflammatory environment and chronic inflammation have long been associated with increased incidence of malignancy and tumor-promoting effect through bioactive molecules. Therefore, using various agents to activate or boost the immune system and attack cancer cells by natural mechanisms through immunotherapy is becoming a powerful clinical strategy to treat cancer. To this end, it is extremely relevant to understand the regulatory mechanisms of inflammation in breast carcinogenesis and metastatic progression to enable identification of novel therapeutic targets for tumors.

In this review, we are discussing the relationship between cytokines recognized as having an important role in TME in breast cancer, such as adipokines and some other cytokines, and how they regulate cancer immunity. It provides a comprehensive overview of cytokine crosstalk, their biological roles, the signaling pathways and transcription factors responsible for the anti- or pro-tumor response and suggested immunotherapeutic strategy for each cytokine for effective treatment of cancer. The details of cytokine overview are described in Table 1.

2. Leptin

Leptin is an obesity-associated adipokine known as the “obesity hormone”, whose circulating levels increase proportionally to body fat mass. It is a pleiotropic cytokine of the IL-6 family produced and expressed mainly by adipose tissue, enterocytes, but also by immune cells, endothelial cells, fibroblasts, CAFs, and some tumor tissues. It is encoded by the obese (Ob) gene which maintains energy homeostasis, through a central feedback mechanism at the hypothalamus. Under normal physiological conditions, leptin plays a key role in the long-term regulation of energy balance by reducing appetite and increasing the metabolism, thereby controlling food intake and body weight. In obese individuals with insulin resistance, high levels of leptin have been correlated with the amount of fat in the body, acting as a pro-inflammatory cytokine and amplifying the insulin resistance process.

Leptin promotes cell proliferation and the development of breast cancers and may be a potential biomarker of breast cancer risk in women, especially overweight/obese or postmenopausal women. Women with elevated serum leptin have a higher risk of breast cancer. Higher levels of leptin have been observed in the invasive stage, from mammary ductal carcinoma in situ to invasive ductal carcinoma, in the cytosol and nuclei of metastatic cells.

In addition, leptin promotes epithelial-to-mesenchymal transition (EMT) by up-regulating the expression of CSC/EMT-related genes, tumor evasion, cell migration, tumor size, overexpression of estrogen and progesterone receptors, protection of malignant cells from apoptosis, and breast cancer metastasis. The functions of leptin are enhanced by the cross-talk with multiple cytokines. Indeed, it is an important mediator of interactions between breast cancer cells and TAMs by stimulating the production of IL-8 which is directly involved in tumor growth.

The molecular actions of leptin are mediated by ObR (leptin receptor), a large membrane protein member of the class I cytokine receptors. Following leptin binding to its receptor (Lep/ObR), Janus kinase 2 (JAK2) becomes activated through autophosphorylation, which in turn phosphorylates tyrosine residues on the intracellular domain of the receptor for the signal transducer and activator of transcription 3 (STAT3). STAT3 forms dimers and translocates into the nucleus where it activates the transcription of different target genes involved in cellular activation, proliferation, and differentiation. Phosphorylated JAK2 also activates other pathways, including mitogen-activated-protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) promoting cell proliferation and differentiation and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/Rac that mediates the regulation of cell cycle, growth, proliferation, and energy metabolism. It also activates the hypoxia-inducible factor-1α (HIF-1α) and NF-κB to regulate the vascular endothelial growth factor (VEGF) and then promotes angiogenesis in mammary tumors. In addition, it activates reactive oxygen species (ROS) production in human epithelial mammary cells, and can regulate metabolic reprogramming to promote cellular growth (Figure 1 and Figure 2).

Leptin-targeting drugs can affect different cell types, including endothelial cells, adipocytes, cancer cells with a less aggressive phenotype, and immune cells by decreasing macrophage recruitment, phagocytic activity, and cytokine production. Thus, the use of antibodies targeting leptin/Ob-R able to perform an antagonist activity could be used in breast cancer therapy. For example, researchers blocked leptin signaling by a leptin peptide receptor antagonist that simultaneously decreased VEGF/VEGFR2 and IL-1 levels, or by producing a synthetic farnesoid X receptor (FXR) (regulator of the dialogue between breast cancer cells and cancer-associated fibroblasts) agonist GW4064, which affects the tumor-promoting activities of CAFs in breast malignancy. Some new super active leptin antagonists (D23L/L39A/D40A/F41A) exhibited more than 60-fold binding to the leptin receptor. In breast cancer, a leptin antagonist-honokiol, a bioactive polyphenol from Magnolia grandiflora, is reported to activate the liver kinase B1-miR-34a axis and finally inhibit EMT.

3. TNFα

TNFα is a major inflammatory cytokine and adipokine described as a circulating and endotoxin-induced factor of hemorrhagic tumor necrosis when present in high concentrations. It is mainly produced by macrophages and in a lower extent by B and T (cytotoxic CD8+ and CD4+ Th1) cells, NK cells, mast cells, fibroblasts, osteoclasts, endothelial, and muscle cells. It can act both in autocrine and paracrine signaling. In general, as an adipokine, it is associated with obesity, promotes insulin resistance and type 2 diabetes. By regulating many cellular and biological processes, it may also have an impact on the endocrine functions of adipose tissue. It can reduce adiponectin secretion, inhibit carbohydrate metabolism, lipogenesis and adipogenesis, and stimulate lipolysis. As a cytokine, it is released by macrophages to alert other cells of the immune system as part of an inflammatory response. Thus, it is involved in the generation of a pro-inflammatory response, as it can activate and up-regulate more than 400 inflammatory genes and stimulate many different cellular responses, such as transcription of pro-inflammatory genes of inflammatory cytokines and chemokines.

TNFα has a key role in breast cancer. It is involved in breast cancer cell survival and/or proliferation, tumor-promoting, aggressiveness, tumor-promoting macrophage infiltration, CAF phenotype, inflammatory chemokine expression, such as C-X-C motif ligand 8 (CXCL8 = IL-8), and angiogenesis. The prometastatic role of TNFα and its involvement in the EMT process required tumor cell migration to establish breast cancer metastasis and its over-expression has often been associated with aggressive cancer behavior and poor prognosis. TNFα and IL-1β are the essential pro-inflammatory cytokines often found in TME. In breast cancer, inflammation is known to be associated with poor prognosis and higher risk of recurrence in patients. TNF-α production by peripheral blood T cells in patients with inflammatory breast cancer was positively correlated with the detection of circulating tumor cells expressing EMT markers. TNFα is recognized by a variety of stromal cells, mainly by TAMs, adipocytes, epithelial and malignant cancer cells themselves. In addition, TNFα and IL-6 have been positively correlated with aromatase activity in human breast adipose tissue in primary culture by increasing aromatase mRNA.

Ultimately, TNFα binds to two different receptors, TNFR1 and TNFR2, and is capable of activating NF-κB, c-Jun, activating protein-1 (AP1), MAPKs, Akt, TAZ, and c-Jun N-terminal kinase (JNK)/P38. TAZ is a transcriptional coactivator, activated via NF-κB to induce tumor initiation and self-renewal in breast cancer stem-like cells, a subpopulation of primary breast tumor cells with differentiation and self-renewal capacities implicated in tumor generation, cancer relapse, and metastasis. TNFα expression is transcriptionally induced by NF-κB, c-Jun, AP1, and nuclear factor associated with activated T cells (NFAT). Ligand-occupied TNFR1 induces NF-κB and c-Jun activations, which inhibit apoptosis, increase transcription of survival factors (Bcl-2), transcription of pro-inflammatory genes, cell death pathways through apoptosis (apoptosis signaling kinase 1 ASK1) or necroptosis, promote transcription of EMT-related factors (i.e., matrix metallopeptidase-2 [MMP2], MMP9), and decrease E-cadherin transcription. However, TNFR2 can activate NF-κB through a pathway similar to that of TNFR1, but it can also activate endothelial/epithelial tyrosine kinase phosphorylation that can activate the Akt pathway. In particular, prolonged exposure of breast cancer cell lines to TNFα induces EMT through the activation of IKKβ and NF-κB, cancer cell migration via the MAPK/ERK signaling pathway, and MMP2 and MMP9 expression. TNFα has been shown to induce the gene expression of aromatase in undifferentiated adipose fibroblasts via c-Fos and c-Jun, and inhibits adipogenic differentiation in breast TME. However, IL-10, through inhibition of TNFα induction, can suppress aromatase mRNA expression in human adipose tissue (Figure 1 and Figure 2).

TNFα can induce resistance to breast cancer therapies, such as ionizing radiation therapy and chemotherapy. In breast cancer, TNFα inhibition has been shown to increase the sensitivity to doxorubicin. TNFα mediates TNFR1-dependent IL-17 production by CD4+ T cells and can promote the activities of immune and cancer cells within tumors. Targeting TNFR2 with antagonistic antibodies (anti-PD-1) has been shown to inhibit the proliferation of cancer cells and tumor-associated Tregs. Therefore, blocking TNFα or its receptors may have significant anti-tumor effects and inhibition of TNFα on tumorigenesis can be positive depending on the immune microenvironment and TNFα concentration.

4. Interleukin-1β (IL-1β)

IL-1β, known as an endogenous mediator of leukocytes, is a potent pro-inflammatory cytokine involved in the modulation of autoimmune inflammation, proinflammatory response, cell proliferation, and cell differentiation. IL1-β gene transcription in macrophages is mainly induced by lipopolysaccharides (LPS) via toll-like receptors (TLRs) or IL-1β itself and by TNFα via the TNF receptors, which are capable of activating NF-κB and subsequently STAT1 pathway. This cytokine is primarily produced by activated macrophages as a proprotein called pro-IL-1β, an inactive precursor. It is proteolytically processed to its active form IL-1β by inflammatory caspase 1 cleavage (CASP1/ICE) and subsequently binds to IL-1 receptor CD121a/IL1R1 and CD121b/IL1R2 subunits. It can also be produced and secreted by a variety of cell types, such as adipocytes, monocytes, DCs, fibroblasts, B cells, TAMs, and some cancer cells to enhance tumor-promotion.

In the TME, IL-1β is up-regulated in many solid tumors, including breast cancers. IL-1β has been reported to control tumor invasion, up-regulate the initiation and development of primary tumor, increase the aggressivity of luminal breast cancer cells, and increase IL-6 production through NF-κB pathway leading to tumor growth and aggressiveness. IL-1β has been linked with poor prognosis in breast cancer and plays a critical role in the recruitment and maturation of adaptive T cell-mediated immunity including CD4+ and CD8+ T cells and myeloid cells. IL-1β also activates focal adhesion kinase and Src to induce MMP9 production and invasion of MCF-7 breast cancer cells. In vitro studies have recently shown that primary breast cancer cells cocultured with monocytes exhibit increased IL-1β, IL-8, and MMPs, suggesting that inflammation and subsequent recruitment of immune cells promote breast cancer development at early stages. Furthermore, in a spontaneous in vivo model of breast cancer, cancer cells stimulate systemic inflammation by producing IL-1β, which leads to stimulation of IL-17 production by γδT cells and can inhibit anti-tumor CD8+ T cell activity. TAM-derived IL-1β can increase cyclo-oxygenase-2 (COX-2) expression in breast cancer cells and contribute to cancer progression, migration/invasion, regulate metastatic process, and EMT.

M2-type macrophages, TAMs and cancer cells can stimulate IL-1β production and subsequently, IL-1β increases macrophage recruitment through the expression of monocyte chemoattractant protein (MCP)-1, which can be polarized into TAM and promote cancer, tumor growth, and metastasis. M1-type macrophages are the cells most frequently induced to produce IL-1β, and subsequently stimulate proinflammatory mediators, the production of angiopoietin-like 4 (ANGPTL4), and VEGF-A in adipocytes, MMP9, and matrix-remodeling activities. In this context, obesity induces secretion of MCP1 and IL-1β by adipocytes associated with breast tissue, which increases macrophage recruitment and the formation of crown-like structures (CLS), followed by the secretion of CXCL12, a key effector responsible for stromal vascularization and angiogenesis. In addition, it promotes activation of PI3K/Rac 1-regulated, ERK1/2 and AP-1, and the reorganization of the actin cytoskeleton in invasive cancer cells (Figure 1 and Figure 2).

Overall, IL-1β represents a major upstream cytokine. Inhibition of IL-1β signaling in malignant tumors are now considered as potential targets for cancer therapy. Anti-IL-1β therapy is shown to decrease metastasis, invasiveness, inflammation-mediated immunosuppression concomitantly with increased anti-tumor immunity response. In breast cancer, a variety of drugs are currently used in clinical practice to target the IL-1 signaling pathway, including anakinra (Nbib1802970), the standard of care used for phase I metastatic breast cancer, and PDR001 (Nbib2900664), in combination with CJM112, EGF816, Ilaris (canakinumab), or Mekinist (trametinib) used for triple-negative phase I and phase II breast cancer.

5. Interleukin-6 (IL-6)

IL-6 is a multifunctional cytokine and an adipokine that clearly has both tumor-promoting and pro-inflammatory effects. It was originally identified as B cell stimulating factor-2 (BSF-2) and the inducer of immunoglobulin production.

IL-6 is produced by non-malignant cells, such as monocytes, macrophages, T cells, B cells, fibroblasts, endothelial cells, and adipocytes. IL-6 transcription is induced by various stimuli, such as TNFα and ROS. It promotes Th2 differentiation and simultaneously inhibits Th1 polarization, maintains dynamic balance between Th1 and Th2 immune cells, and regulates the balance between IL-17-producing Th17 cells and Treg. In the TME, its main sources are some cancer cells, TAMs, myeloid-derived suppressor cells (MDSC), Th2 cells, and CAFs.

IL-6 is a major player in chronic inflammatory diseases, autoimmune diseases, cancer, and tumor immunity. In breast cancer, IL-6 is found to be overexpressed and has been described as a tumor-promoting cytokine through its major effector STAT3. It is a key factor in malignancy by promoting cell growth (via the suppression of apoptosis and promotion of angiogenesis), macrophage polarization, tumor initiation, progression, and metastasis, by selectively recruiting mesenchymal stem cells to sites of carcinoma growth where they interact with breast cancer stem cells. IL-6 controls cancer stem cell renewal and induces cancer cell migration, and EMT. IL-6 stimulates aromatase and therefore estrogen biosynthesis, thus contributing to hormone-dependent breast cancer. CAFs in breast tumors express high levels of IL-6 and subsequently mediate epithelial-stromal interactions to promote tumorigenesis. High IL-6 levels in breast cancer tissues maintain the aggressive phenotype.

The IL-6 receptor (IL-6R) is a hetero-trimeric complex receptor composed of an IL-6-binding receptor molecule α-subunit (gp80) and two signal transducing β-subunits of glycoprotein 130 (gp130). Classical IL-6 signaling is initiated by its binding to IL-6Rα (present either on the cell surface or in secreted form, which then induces cis dimerization of gp130, auto- and trans-phosphorylation and activation of the associated JAK1, JAK2, and tyrosine kinase 2 (TYK2). The tyrosine residues phosphorylated by JAKs in the intracellular domain of gp130 activate the transcription factors STAT3/STAT1, Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), ERK, MAPK, and PI3K signaling pathways. Thus, STAT3 may mediate tumorigenesis by increasing cell-cycle progression, resistance to apoptosis (inducing the expression of BCL2, BCL-XL, and survivin), metastasis, and senescence. In addition, IL-6/STAT3 signaling activates the transcription of target genes, including the proto-oncogenes c-myc, JunB, cFos, and mTORC1 metabolic regulators. It also blocks DC differentiation, thereby preventing T cell activation and inducing T cell death. Activation of STAT3 in tumor-associated endothelial cells, TAMs, and cancer cells, induces their ability to express basic fibroblast growth factor (bFGF) and VEGF, promoting rapid vascularization. Indeed, IL-6 may up-regulate circulating VEGF in breast cancer patients and promote angiogenesis and metastasis. IL-6 may promote the mobilization of anti-tumor CD8+ effector T cell responses, the development of APC, such as DCs and cytotoxic T cells, as well as the survival, proliferation, differentiation, and recruitment of leukocytes. Activation of IL-6Rα expressed on DCs can act directly on CD4+ T cells through gp130 and subsequently induce Th17 cells. Furthermore, it has been shown that high expression of IL-6Rα induces resistance to apoptosis in breast cancer (Figure 1 and Figure 2).

Therefore, blocking IL-6 (i.e., anti-IL-6 therapy), targeting its receptor in combination with signaling from other anticancer therapies, and targeting the IL-6-STAT3 axis is a potential therapeutic strategy that may be beneficial in the treatment of breast cancer. Down-regulation of IL-6 is linked to a better response to breast cancer treatment and a recent study showed that the IL-6R neutralizing antibody, tocilizumab, abrogated IL-6 signaling in breast cancer. A synthetic anti-gp130 compound (bazedoxifene) inhibited IL-6-induced growth of breast cancer cell lines and down-regulated STAT3 phosphorylation. An IL-6R antagonist (Tocilizumab) for trastuzumab-resistant HER2-positive metastatic breast cancer is being evaluated in a clinical trial (NCT03135171).

6. Interleukin-8 (IL-8)

IL-8, also known as CXCL8, is a proinflammatory chemokine, produced and expressed by monocytes, macrophages, neutrophils, T cells, fibroblasts, epithelial cells, and vascular endothelial cells. It is known as neutrophil chemotactic factor inducing neutrophil and granulocytes recruitment, degranulation, and phagocytosis. IL-8 has been associated with proinflammatory response in obesity and cancer and can induce the recruitment of inflammatory cells and oxidative stress mediators into localized inflammation to exert cytotoxic activities.

IL-8 secretion by TAMs, CAFs, and some cancer cells promotes their recruitment, proliferation, and survival, suppresses CD8+ T cell activity, and stimulates cellular secretion of additional growth factors that contribute to breast cancer progression. Several studies have shown that in breast cancer cell lines, invasion is directly proportional to IL-8 expression where, various cytokines, such as IL-1β, TNFα, and IL-6, as well as hormones, such as progesterone and estrogen, are thought to up-regulate IL-8 expression in breast cancer cells compared to normal breast tissue. Breast cancer cells are reported to secrete IL-8, express CXCR1/2, and promote breast cancer initiation and progression, as well as tumor cell migration and invasion.

Cellular responses to IL-8 are mediated by two cell-surface G protein-coupled serpentine receptors for a group of C-X-C chemokines, termed CXCR1 and CXCR2. CXCR1 is specific for IL-8, whereas CXCR2 can mediate cellular responses after binding other chemokines as well, such as IL-2 and IL-6. IL-8 expression can be regulated by a variety of stimuli, including inflammatory signals (e.g., TNFα, IL-1β), environmental and chemical stresses (e.g., hypoxia or exposure to chemotherapy agents), and steroid hormones

IL-8 signaling can activate and regulate PI3K (in neutrophils), PKB/Akt, MAPK (cell proliferation in neutrophils, endothelial, and in some breast cancer cell lines) and the Raf-1/MAP/ERK1 cascade, p38 MAPK signaling cascade and phospholipase C. In addition, it can activate Src, focal adhesion kinase FAK, STAT3, JAK2/STAT3/Snail (in cancer cells), signaling kinases correlated with cancer progression. Thus, it forms an immunosuppressive microenvironment to enhance tumorigenicity, cancer cell motility (via MMP9 expression, PI3K-Akt signaling, and E-cadherin down-regulation), EMT, invasion and metastasis. In addition, it can activate endothelial cells in the tumor to promote vascular endothelial cell proliferation and angiogenesis. IL-8 receptors on endothelial cells can activate Ras/PI3K, NF-κB/VEGF activation, chemoresistance, and metastasis (Figure 1 and Figure 2).

The multiple effects of IL-8 signaling on different cell types present in the TME suggest that targeting CXC chemokine signaling (including, but not limited to IL-8) may have important implications for halting disease progression and helping to sensitize tumors to chemotherapeutic and biologic agents. Furthermore, a clinical study has shown that elevated serum IL-8 levels correlate with higher-stage breast tumors, invasiveness and poor prognosis. CXCL8-CXCR1/2, as a key driver of immune suppression, may interfere with the differentiation and function of stromal and immune cells in the TME, ultimately affecting immunotherapy. Therefore, blocking the CXCL8-CXCR1/2 axis by using small molecules or antibodies were testes, such as SB225002 (CXCL8 inhibitor binding to CXCR2) to inhibit tumor progression in HER2+ breast cancer, and danirixin (GSK1325756) to suppress cancer migration, invasion, and metastasis. Finally, various orally active small-molecule non-competitive antagonists of CXCR1 and CXCR2, such as SCH527123 (Merck), repertaxin (Dompé, Milan, Italy), and SCH479833 (Merck, Whitehouse Station, NJ, USA), have demonstrated anti-tumor effects in breast cancer xenograft models.

7. Interleukin-17A (IL-17A)

IL-17A is the founding member of the IL-17 family of pro-inflammatory cytokines associated with allergic responses. In humans, increased IL-17A level is associated with infections, antimicrobial immunity, chronic inflammatory diseases, obesity, and autoimmune diseases. Following stimulation of CD4+ T cells by cytokines, such as IL-6, TNFα, IL-21, IL-23, TGF-β, and IL-1β, a naïve CD4+ T cell differentiates into an inflammatory class of Th17 cells and secretes IL-17A. It is primarily produced by a group of Th cells known as Th17 cells, in response to their stimulation by IL-23. It is also produced by other cells, such as CD8+ T cells, γδ T cells, NKT, and NK cells. Both STAT3 and NF-κB signaling pathways are required for this cytokine-mediated IL-17 production. Additionally, the RAR-related orphan nuclear receptor-γt (RORγt) is the most specific transcription factor promoting Th17 cell differentiation. The most notable role of IL-17 is its involvement in the induction and mediation of proinflammatory responses under inflammatory conditions through the stimulation of many cell types (macrophages, fibroblasts, endothelial cells) to produce other cytokines, such as TNFα, IL-1β, IL-6, CSF, TGF-β, and chemokines, including IL-8 to amplify the inflammatory response.

Biologically active IL-17A interacts with the type I single-pass transmembrane protein, IL-17R cell surface receptor. It can be expressed by T cells, macrophages, fibroblasts, endothelial, epithelial, and cancer cells. Following binding to its receptor, IL-17 activates several signaling cascades that, in turn, lead to the induction of chemokines and the recruitment of immune cells, such as neutrophils and monocytes to the site of inflammation. It stabilizes RORγt important pathways that have become a focus around the IL-17 cytokine family, including NF-κB, and the production of IL-6 and TGFβ, and IL-1β signaling pathways that induce the expression of several proinflammatory cytokines.

High levels of IL-17A in the breast microenvironment are associated with the highly invasive and aggressive phenotype of breast cancer. IL-17A induces activation of ERK1/2 phosphorylation, p38 MAPK and STAT3 (IL-6-STAT3) signaling pathways, and promotes tumor growth, tissue invasion, tissue-remodeling and matrix degrading substances (such as MMPs, including MMP2 and MMP9), migration, inhibition of apoptosis, and angiogenesis (via activation of VEGF and CXCL8 expression). IL-17A can stimulate breast tumorigenesis and, in turn, CAFs, γδT and breast tumor cells increase Th17 cell recruitment and IL-17A production. Tumor-derived IL1β activates γδ T to produce high levels of IL-17, which leads to neutrophil expansion and altered neutrophil phenotype. Neutrophils produce inducible nitric oxide synthase (iNOS), which inhibits the activity of anti-tumor CD8+ T-cells and subsequently stimulates cancer progression, migration, invasion, and metastasis. Interestingly, IL-17 increases expression of MMP-9, indoleamine 2,3-dioxygenase, COX-2, and MMP-13. furthermore, IL-17 up-regulates the gene expression corresponding to M2-type TAMs. IL-17 acts alone or in synergy with other stimuli (such as TNFα and IFN-γ) to activate the expression of many genes, including cytokines, such as IL-6, IL-19, IL-20, IL-24, TNFα, and granulocyte-CSF, chemokines, such as IL-8, CXCL1, CXCL2, CXCL5, CXCL9, CXCL10, C-C motif ligand 2 (CCL2), CCL7, and CCL20, MMP13, receptor activator of nuclear factor kappa-B ligand (RANKL), and antimicrobial peptides (lipocalin 2, β-defensin-2, S100A7, and S100A8/9) (Figure 1 and Figure 2).

A better understanding of the character of Th17 cells in tumor immunity should generate opportunities for the progression of new therapeutic approaches for cancer patients. Therefore, different strategies should be used depending on the type of cancer and the clinical influence of IL-17 in tumor development. For example, the use of neutralizing antibodies against Th17-related cytokines has been shown to decrease EMT and significantly inhibit progression and metastasis of lung cancer and control invasive breast tumors. Similarly, because the absence of γδ T cells or neutrophils profoundly reduces metastasis without influencing primary tumor progression, regulation of the Treg/Th17 axis, inhibition of the γδ/IL-17/neutrophil axis, and blockade of IL-17RB in cancer cells could be an effective therapeutic approach in breast cancer.

8. Interleukin-23 (IL-23)

IL-23 is a heterodimeric proinflammatory cytokine that belongs to the IL-12 cytokine family. These two share a common p40 subunit that is covalently linked either to p35 subunit to form IL-12 or to p19 subunit to form IL-23. It is a key cytokine for the differentiation, maintenance, and expansion of Th17 cell, as discussed earlier. IL-23 is mainly produced by DCs and macrophages, but also by monocytes, neutrophils, innate lymphoid cells, γδ T cells, B cells, and M2/TAM cells. The heterodimeric IL-23 cytokine receptor is composed of IL12Rβ1 (receptor for IL-12) that signals through tyrosine kinase-2 (TYK2), and IL-23R that signals through JAK2 to activate STAT3. IL-23 receptors can be expressed in T cells, NK cells, NKT cells, tumor cells and are weakly expressed on monocytes, macrophages, and DC populations.

Within the immune and inflammatory microenvironment, IL-23 participates in the progression of chronic inflammation and its maintenance and plays a critical role in autoimmune diseases (via IL-23/IL-17 immune axis). Notably, it can manipulate host immune responses and modulate TME cells. IL-23 is a key cytokine for the differentiation, maintenance, and expansion of Th17 cells via activation of STAT3, which in turn stabilizes RORγt, as previously detailed.

It has been identified as a link between tumor-associated inflammation and tumor immune evasion, and can directly affect a variety of premalignant and malignant tumors. IL-23 is involved in breast carcinoma cell metastasis and is associated with higher breast cancer tumor size and stages. The pro-tumorigenic role of IL-23 was first reported by Langowski et al., where its genetic blockade resulted in increased cytotoxic T cell tumor infiltration. It has been shown to activate the NF-κB signaling and then induces immune cell activation which exacerbates inflammation and promotes tumor growth. IL-23 decreases infiltration of Treg and CD8+ T cells to promote the infiltration of M2-type macrophages and neutrophil cells and their overexpression and secretion of pro-tumor immunosuppressive cytokines, such as TGF-β and IL-10. Furthermore, IL-23 increases the expression of endothelial and angiogenic markers, such as VEGF, MMP9, CD31, and the proliferative marker Ki67 in tumors. In turn, mammary tumor cells produce IL-6, VEGF, CCL22 to recruit TAMs, which stimulate IL-23 production and maintain the suppressive activity of Treg in the TME (Figure 1 and Figure 2).

In conclusion, IL-23 has been shown to play multifunctional roles in tumorigenesis by inhibiting anti-tumor effector immunity. It provides an important molecular link between the tumor-promoting inflammatory response and the failure of adaptive immune surveillance to infiltrate tumors. Therefore, injectable IL-23 inhibitor drugs, such as guselkumab/Tremfya, risankizumab-rzaa/Skyrizi and tildrakizumab-asmn/Ilumya, blocking-up the process of IL-23 (M2 and neutrophils), neutralizing antibodies specific to IL-23p19 (G23-8 antibody can down-modulate MMP9 expression and increased surveillance of CD8+ T cells), and IL-23p19 antagonists can provide effective anti-tumor therapy.

9. Interleukin-12 (IL-12)

IL-12 is a member of a small family of heterodimeric pro-inflammatory cytokines, produced and expressed primarily by APCs, such as DCs and activated macrophages, depending on the immune context. Despite its similarities to IL-23, IL-12 may be able to stimulate effector cells of innate and adaptive immunity, activate macrophage polarization to M1 type, and enhance anti-tumor cytotoxic immune responses in the TME. The IL-12 receptor comprises IL-12Rβ1 and IL-12Rβ2 subunits and is commonly expressed in T cells, NK cells, NKT cells, monocytes, macrophages, and DC populations.

Following binding of IL-12 to its receptor expressed on target cells, phosphorylation and homo-dimerization of STAT4 are promoted by JAK2 and TYK2. Therefore, activated STAT4 in CD4+ T cells induces transcription of the transcription factor T-box (T-bet) that can control IFN-γ production by Th1 cells, whereas in combination with STAT4, it enhances transcription of IL-12Rβ1, regulates Th1 cell differentiation and promotes expression and activation of Th1-associated receptors.

IL-12-mediated Th1 activation releases Th1-specific cytokines, including IFN-γ, to solicit and recruit cytotoxic NK and CD8+ T cells. IL-12 promotes the differentiation of naïve CD8+ T cells to the effector phenotype and acts as a CD8+ T-anti-apoptotic factor that can directly destroy microorganisms and cancer cells through the release of perforin and proteolytic enzymes. Overall, IL-12 targets and modulates Th1, CD8+ T, NK, and APC cells that regulate immune surveillance, effective antimicrobial and cytotoxic activity. Thus, it promotes efficient anti-tumor responses, cancer cell elimination, and tumor clearance in many cancers, such as breast cancer, through inhibition of the PI3K/AKT/mTOR signaling pathway. In addition, T-bet and STAT4 down-regulate RORγt, which limits the generation and proliferation of Th17 and Treg within the tumor. Furthermore, it up-regulates MHCI on tumor cells to facilitate self-antigen presentation, increases the production of chemokines, such as CXCL9, CXCL10, CXCL11, and IFN-γ to attract effector immune cells, such as CD8+ T, NKs, and M1 macrophages. In addition, IL-12 can increase the infiltration of IFN-γ-producing NK cells where, mechanistically, activation of IFN-γ signaling inhibits the proliferation of Tregs and subsequently converts them into IFN-γ-producing T cells. Thus, it enhances the body’s immune response against cancer, promotes cancer cell apoptosis, increases MHCI expression on APCs, and down-regulates intratumor VEGF (Figure 1 and Figure 3).

Therefore, IL-12 can be considered a strong candidate for immunotherapy-based interventions. It may be beneficial in controlling tumor growth by activating effective anti-tumor cytotoxic immune responses and killing tumor cells by tumor-specific cytotoxic NK and CD8+ T cells. Recombinant human IL-12 (rhIL-12) is currently in clinical trials for the treatment of cancer and may also play a beneficial role in synergy with chemotherapy (through activation of NK cells) and radiation therapy (reducing complications). Various therapies have been devised. For advanced solid tumors, such as breast, a mRNA-based IL-12 delivery (SAR441000), an mRNA mixture encoding IL-12sc, interferon alpha2b, GM-CSF, and IL-15sushi/ is being evaluated.

10. Interleukin-2 (IL-2)

IL-2 is a pro-inflammatory cytokine, doted of the anti-tumor response. It was firstly identified by Morgan and colleagues in 1976 as “T-cell growth factor” (TCGF). Among other things, IL-2 can modulate the differentiation of CD4+ T cells into Th1 and Th2, increase the cytolytic activity of NKs, induce the development of Treg and cytotoxic T cells (CD8+ T cells), while it can both inhibit the differentiation of Th17, but also stimulate their expansion. In addition, IL-2 promotes autocrine survival and cytolytic activity of T and NK cells in anti-tumor immunity. The main sources of IL-2 are antigen-stimulated CD4+ T cells, but it can also be produced by activated CD8+ T cells, activated DCs, and NK cells.

IL-2 exerts its effects by binding to the IL-2 receptor subunits, IL-2Rα (CD25), IL-2Rβ (CD122), and IL-2Rγ (CD132), with different affinities. The α chain is unique to IL-2 and binds it with low affinity, without transducing a signal because of its short intracellular chain. IL-2Rβ is the key component of the IL-15 receptor, whereas the γ chain is shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Notably, the α chain functions to initially bind IL-2, which localizes it to the cell surface, effectively increasing its concentration and also inducing a conformational change in IL-2R. Heterodimerization of the intermediate (IL-2Rβγ) and high affinity (IL-2Rαβγ) receptor is essential for the activation of several IL-2 transducers and T cell signaling. IL-2Rα can be expressed by naïve T cells (can be triggered rapidly by T cell receptor TCR), activated CD4+ and CD8+ T cells, mature DCs, B cells, and endothelial cells. In addition, Tregs and some NK cells can also express high levels of the α chain after the IL-2 stimulation, allowing them to consume IL-2 more efficiently than CD4+ and CD8+ effector, even at low levels (Figure 2). The IL-2Rβ is mainly expressed by Treg, memory CD8+ T cells, and NK cells. The intracellularly stored IL-2Rγ subunit is expressed primarily by hematopoietic cells, some tumor cells, and by CD4+ T only during activation, whereas the dimeric IL-2Rβγ receptor is expressed by memory CD8+ cells, naïve, T, and NK cells. Tregs and activated T cells express high levels of trimeric IL-2Rαβγ complex.

Further binding of IL-2 to its receptor, IL-2Rβγ or IL-2Rαβγ complex, results in activation of the JAK1 and JAK3, which activate the recruitment and phosphorylation of STAT transcription factors, primarily STAT5, but also STAT1 and STAT3. Subsequently, three major signaling pathways, including PI3K-AKT, JAK-STAT, and MAPK/ERK are activated to mediate cell growth, survival, and differentiation, and cytokine production (IL-4, IL-6, IL-12). Thus, in breast cancer, IL-2 plays an anti-tumor effect due to increased recruitment of IL-2-releasing NK cells and the induction of anti-apoptotic function in CD8+ T cells, the main effector of the antitumor response. IL-2 can promote activation and proliferation of CD8+ T cells in early tumor stage but can deplete CD8+ T cells in late tumor stage (Figure 1).

The multiple effects of IL-2 signaling on the different cell types present in the TME may be beneficial in developing T cells and controlling tumor growth by activating effective antitumor cytotoxic immune responses and killing tumor cells. Thus, IL-2 administration and adoptive transfer of antitumor T cells cultured with IL-2 have represented highly effective therapies in patients with solid human cancers, such as metastatic renal cancer, and melanoma.

11. Interferon-γ (IFN-γ)

IFN-γ is named after its ability to interfere with virus growth. It is a pluripotent cytokine that plays a controversial role in the immunomodulation, anti-microbial/anti-viral host defense, allergies, autoimmune diseases, obesity, and antitumor immunity. It enhances the response to inflammatory molecules (TLR ligands and TNF), cytotoxic function of NK cells, and the number of M1-macrophages to provide phagocytic activity. It is an important autocrine signal in the innate immune response and a paracrine signal in the adaptive response. During inflammation, CD4+ Th1 cells are the main source of IFN-γ that promotes IFN-γ production by Th1 and NK cells. IFN-γ triggers the activation of the proinflammatory response by promoting differentiation of naïve CD4+ T cells into Th1 and Th2 cells, increasing the killing capacity of CD8+ T cells and decreasing the proliferation of Tregs. In DCs, IFN-γ signaling contributes to their maturation, production of IL-12, IL-1β, and activation of CD4+ and CD8+ T-cells. These cells can be stimulated in an inflammatory or tumor microenvironment by antigens secreted by the tumor or pathogen, IFN-γ itself via positive feedback, or IL-12, IL-15, and IL-18 to activate IFN-γ production. IFN-γ has been shown to interact with a heterodimeric receptor composed of two subunits, IFN receptor 1 (IFNGR1) and IFN receptor 2 (IFNGR2), expressed on the surface of nearly all types of cells to regulate the immune response. Secreted IFN-γ binds to its receptor (IFNGR1/2) and can activate the JAK(1/2)-STAT pathway (1/3/4), AP-1 and subsequently the up-regulation of interferon regulatory factor 1 (IRF1) and interferon-stimulated genes (ISGs), including those for MHC presentation.

In the TME, the concentration of IFN-γ determines whether the function will be anti or pro-tumorigenic. A high dose of IFN-γ stimulates JAK-STAT1 signaling and can induce cancer cell death and apoptosis. However, low doses of IFN-γ produced at the tumor site by host-infiltrating cells or during immunotherapy can enhance tumor cell survival, induce risk of metastasis and expression of EMT transcription factors via activation of ICAM1-PI3K-Akt-Notch1 signaling in cancer cells. IFN-γ production by NK, NKT, CD8+ T, Th1, and γδ T cells stimulates and enhances immunorecognition, recruitment of immune cells to tumor sites and subsequently increases the ability to kill tumor cells, by improving the anti-proliferative status of cancer cells (growth inhibition, cell death, autophagy), tumor cell antigenicity, and metastasis reduction by up-regulating fibronectin. IFN-γ arrests the cell cycle and initiates apoptosis in tumor cells (up-regulation of p21 and p27, granzyme B and perforin). In addition, IFN-γ can increase the destruction of established tumor-associated blood vessels, inhibit the migration of TAMs to enhance the efficacy of anti-PD1 antibody therapy (Figure 1, Figure 2 and Figure 3).

Chronic high-dose IFN-γ release, loss of the IFN-γ receptor, prolonged IFN-γ signaling in tumor cells, and PD-L1 expression (cancer and immune infiltrating cells), may induce apoptosis in CD4+ T-cells, suppress immune and secondary antitumor immune response, cause immune evasion adaptive immune resistance to immune checkpoint therapy. Therefore, IFN-γ is believed to be one of the critical factors determining the success of immunotherapy because dysregulation of IFN-γ responsiveness and/or signaling is often associated with resistance to immunotherapy.

12. Interleukin 10 (IL-10)

IL-10 is known as human cytokine synthesis inhibitory factor, with multiple and pleiotropic effects in immunoregulation, infection, inflammation, autoimmunity, transplantation, and tumorigenesis. It is a cytokine with potent anti-inflammatory properties by repressing the expression of inflammatory cytokines, such as TNF-α, IL-6, and IL-1 and is considered one of the most crucial immunosuppressive cytokines in tumor progression. In general, IL-10 is mainly produced by Th2, Th1, Treg, and Th17, and also by CD8+ T cells, monocytes, macrophages, DCs, B cells, mast cells, eosinophils, keratinocytes, epithelial cells, and even some tumor cells. The IL-10-producing cell type depends on the inducing stimulus, e.g., Th1, Th17 cells, and macrophages represent an important source of IL-10 in infectious diseases.

IL-10 receptor is a two-receptor complex consisting of two copies of IL-10 receptor 1 (IL-10R1) and IL-10R2. Both subunits belong to the class II cytokine receptor family. IL-10R1 forms specific high-affinity interactions with IL-10, whereas IL-10R2 is a shared low-affinity receptor that participates in receptor complexes with other cytokines, such as IL-22, IL-26, IL-28, IFN-γ, and IL-29, which play critical roles in host defense. DCs, T cells, B cells, NK, Treg, and mast cells express IL-10R1, whereas the IL-10R2 subunit is ubiquitously expressed. In humans, IL-10 first binds to IL10R1, and then this complex binds to IL10R2, forming a heterotetramer (two IL10R1/two IL10R2), allowing the assembly of the IL-10R complex, which is the first step in the initiation of IL-10 signaling pathways. Once the complex is assembled, Jak1 and Tyk2 associated with IL-10R1 and IL-10R2, respectively, are activated and phosphorylate the intracellular cytoplasmic tails of the IL10R1 subunit. This results in the recruitment and phosphorylation/activation of STAT3 and STAT1 or STAT5 under certain conditions. STAT3 is most notably associated with IL-10 signaling, recruited to IL-10R1 upon IL-10 binding, driving the expression of anti-inflammatory mediators that block various inflammatory pathways. The silencing of STAT3 and suppressor of cytokine signaling 3 (SOCS3) protein reduces the IL-10 expression. In addition, IL-10 is involved in MAPK inhibition and/or activation of a PI3K/AKT inhibitory pathway and can inhibit NF-κB translocation to the nucleus and DNA binding, whereas hyper induction and production of high levels of IL-10 are due to MAPK/ERK activation. In macrophages, IL-10 activates the PI3K/Akt/GSK3 β-signaling cascade and modulates downstream transcription and PI3K-mediated mTORC1 activity in monocytes. The IL10 response leads to the expression of anti-inflammatory mediators that block various inflammatory pathways, therefore has prominent role in regulating intestinal inflammation, tumor immunosuppression, viral infection, allergic reactions. For example, IL-10 down-regulates the expression of co-stimulatory molecules on macrophages, differentiation and maturation of DCs, activation of CD4+ Tcells. It also inhibits the production of proinflammatory cytokines such as IL-1β, IL-6, IL-8, IL-12, IL-18, CSF, and TNF-α, suppresses Th1-associated cytokines (IL-2, IFN-γ), and stimulates B and NK cell survival and proliferation, as well as their production of antibodies and cytokines.

The role of IL-10 in modulating the tumor immune response appears to be dependent on the TME and the number of IL-10 receptors expressed on immune cells. IL10 is primarily produced and expressed by M2/TAM, lymphocytes and cancer cells. It contributes positively to tumor growth and promotion (STAT3 in cancer cells), angiogenesis, tumor escape, and metastasis. Furthermore, IL-10 levels increases TGF-β excretion in Treg cells and macrophages and then promotes EMT. Similarly, TGF-β in combination with IL-6, induces IL-10 secretion by Th-17 cells. In addition, IL-10 can suppress T-cell proliferation and activity in breast cancer and inhibit T-cell-stimulated anti-tumor immunity by down-regulating MHC class II (APC). IL-10 produced by TAMs and activation of the IL-10/STAT3/BCL-2 signaling pathway have been reported to contribute to therapeutic resistance in irradiation, chemotherapy and immunotherapy (Figure 1 and Figure 2).

Therefore, targeting IL-10 may provide a new therapeutic opportunity for cancer. The use of PEG-IL-10 (pegilodecakin) and anti-PD-1 (pembrolizumab or nivolumab)) treatment to suppress Il-10 signaling or PEGylated human IL-10 (PEG-rhuIL-10), has been designed for clinical use in patients with advanced solid tumors. These strategies are effective in stimulating IFN-γ secretion, perforin, and granzyme B production by CD8+ T cells and decreasing TGFβ levels.

13. Conclusions

The microenvironment significantly affects immune cell response, activation, differentiation, and cytokine secretion. It can enhance the pro- and antitumorigenic response, mediate inflammation and oncogenesis depending on cytokine interference. Many solid tumors, including breast cancer, are composed of heterogeneous cell populations that interact in complex networks through a mixture of cytokines. These are generated by innate or adaptive immune cells, immunocompetent cells, stromal cells, and some cancer cells to inhibit tumor growth, such as IL-2, IL-12, IFNs, or promote tumorigenesis, proliferation, and/or invasion, such as, IL-23, IL-17, TGF- β, IL-10, and some adipokines including leptin, TNFα, IL-1β, and IL-6. Adipokines may contribute to an obesity-related state of low-grade inflammation, regulate energy expenditure, inflammation, cancer growth, progression, and metastasis. Therefore, inflammatory cytokines generated by cancer-associated cells, such as TAMs, CAFs, Th17s, and Tregs, can be expressed by both immune and cancer cells and promote breast cancer, and especially cancer-associated inflammation, such as obesity-associated breast cancer. Thus, they induce tumor-associated inflammation, proliferation, survival, progression, escape, migration, invasiveness, and metastasis of cancer. They decrease the infiltration of Th1, CD8+ T cells, NKs, Tregs, promote the infiltration of Th2, M2/TAMs and CAFs and their secretion of pro-tumor immunosuppressive cytokines. Figure 2 summarizes the crosstalk and the immunoregulation between all of these actors. Although they can be activated, such as JAK/STAT, PI3K, AKT, Rac, MAPK, JunB, cFos, and mTORC, involved in the activation of proliferation, survival, differentiation, and cell migration, NF-κB, JNK, and P38 are involved in inflammation, metastatic protein (MMP, COX-2), and anti-apoptotic protein (Bcl-XL). Thus, it forms an immunosuppressive microenvironment to enhance tumorigenicity, cancer cell motility (via MMP9 expression, PI3K-Akt signaling), EMT (FoxC1 in cancer cells), and angiogenesis (activation of Ras/MAPK/PI3K, NF-κB/VEGF). In the Figure 1, TYK2-mediated JAK/STAT signaling network is represented. Moreover, for tumor clearance and effective anti-tumor responses, many cytokines attract effector immune cells, such as NKs, NKTs, M1s, CD8+ T cells, APC, and Th1, to regulate immune surveillance, cytotoxic activity, and anti-apoptotic factors for CD8+ T cells. In addition, they can stimulate the secretion of perforin, proteolytic enzymes, and cell adhesion molecules and inhibit tumor induced Treg cells that suppress effector T cells and impair the body’s immune response against cancer. Because of the critical role of cytokines in the progression of various disorders, such as cancer, understanding the crosstalk between cytokines can provide important insights into immune-related mechanisms of cancer development, and this knowledge can then be applied to cancer treatment.

References 444

  1. 1.
    γδ T Cells: The Ideal Tool for Cancer Immunotherapy · 2020
    No notice
  2. 2.

    Chaplin D.D. Overview of the immune response. J. Allergy Clin. Immunol. 2010;125:S3-S23.

    Not in our library10.1016/j.jaci.2009.12.980

  3. 3.

    Deng T., Lyon C.J., Minze L.J., Lin J., Zou J., Liu J.Z., Ren Y., Yin Z., Hamilton D.J., Reardon P.R., et al. Class II Major Histocompatibility Complex Plays an Essential Role in Obesity-Induced Adipose Inflammation. Cell Metab. 2013;17:411-422.

    Not in our library10.1016/j.cmet.2013.02.009

  4. 4.

    Ohue Y., Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci. 2019;110:2080-2089.

    Not in our library10.1111/cas.14069

  5. 5.
    Neutrophils in cancer carcinogenesis and metastasis · 2021
    No notice
  6. 6.

    Habanjar O., Diab-Assaf M., Caldefie-Chezet F., Delort L. The Impact of Obesity, Adipose Tissue, and Tumor Microenvironment on Macrophage Polarization and Metastasis. Biology. 2022;11:339.

    Not in our library10.3390/biology11020339

  7. 7.

    Zhang J.-M., An J. Cytokines, Inflammation, and Pain. Int. Anesthesiol. Clin. 2007;45:27-37.

    Not in our library10.1097/aia.0b013e318034194e

  8. 8.

    Raman D., Sobolik-Delmaire T., Richmond A. Chemokines in health and disease. Exp. Cell Res. 2011;317:575-589.

    Not in our library10.1016/j.yexcr.2011.01.005

  9. 9.

    Bachelerie F., Ben-Baruch A., Burkhardt A.M., Combadiere C., Farber J.M., Graham G.J., Horuk R., Sparre-Ulrich A.H., Locati M., Luster A.D., et al. International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors. Pharmacol. Rev. 2014;66:1-79.

    Not in our library10.1124/pr.113.007724

  10. 10.

    Mélik-Parsadaniantz S., Rostène W. Chemokines and neuromodulation. J. Neuroimmunol. 2008;198:62-68.

    Not in our library10.1016/j.jneuroim.2008.04.022

  11. 11.

    Zlotnik A., Yoshie O. The Chemokine Superfamily Revisited. Immunity. 2012;36:705-716.

    Not in our library10.1016/j.immuni.2012.05.008

  12. 12.
    The role of interleukin-1 in general pathology · 2019
    No notice
  13. 13.

    Akdis M., Burgler S., Crameri R., Eiwegger T., Fujita H., Gomez E., Klunker S., Meyer N., O’Mahony L., Palomares O., et al. Interleukins, from 1 to 37, and interferon-γ: Receptors, functions, and roles in diseases. J. Allergy Clin. Immunol. 2011;127:701-721.e70.

    Not in our library10.1016/j.jaci.2010.11.050

  14. 14.

    Shin E., Koo J.S. The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis. Int. J. Mol. Sci. 2020;21:4967.

    Not in our library10.3390/ijms21144967

  15. 15.

    Blüher M., Mantzoros C.S. From leptin to other adipokines in health and disease: Facts and expectations at the beginning of the 21st century. Metabolism. 2015;64:131-145.

    Not in our library10.1016/j.metabol.2014.10.016

  16. 16.

    Mancuso P. The role of adipokines in chronic inflammation. ImmunoTargets Ther. 2016;2016:47-56.

    Not in our library10.2147/itt.s73223

  17. 17.

    Barchetta I., Cimini F.A., Ciccarelli G., Baroni M.G., Cavallo M.G. Sick fat: The good and the bad of old and new circulating markers of adipose tissue inflammation. J. Endocrinol. Investig. 2019;42:1257-1272.

    Not in our library10.1007/s40618-019-01052-3

  18. 18.

    Nehme R., Diab-Assaf M., Decombat C., Delort L., Caldefie-Chezet F. Targeting Adiponectin in Breast Cancer. Biomedicines. 2022;10:2958.

    Not in our library10.3390/biomedicines10112958

  19. 19.

    Artac M., Altundag K. Leptin and breast cancer: An overview. Med. Oncol. 2012;29:1510-1514.

    Not in our library10.1007/s12032-011-0056-0

  20. 20.

    Ferrer I. Transforming growth factor-α (TGF-α) and epidermal growth factor-receptor (EGF-R) immunoreactivity in normal and pathologic brain. Prog. Neurobiol. 1996;49:99-119.

    Not in our library10.1016/0301-0082(96)00009-3

  21. 21.

    MaruYama T., Chen W., Shibata H. TGF-β and Cancer Immunotherapy. Biol. Pharm. Bull. 2022;45:155-161.

    Not in our library10.1248/bpb.b21-00966

  22. 22.

    Tamimi R.M., Brugge J.S., Freedman M.L., Miron A., Iglehart J.D., Colditz G.A., Hankinson S.E. Circulating Colony Stimulating Factor-1 and Breast Cancer Risk. Cancer Res. 2008;68:18-21.

    Not in our library10.1158/0008-5472.can-07-3234

  23. 23.

    Balkwill F. Tumour necrosis factor and cancer. Nat. Rev. Cancer. 2009;9:361-371.

    Not in our library10.1038/nrc2628

  24. 24.

    Isaacs A., Lindenmann J. Virus interference. I. The interferon. Proc. R. Soc. Lond. Ser. B-Biol. Sci. 1957;147:258-267.

    Not in our library10.1098/rspb.1957.0048

  25. 25.

    Schroder K., Hertzog P.J., Ravasi T., Hume D.A. Interferon-γ: An overview of signals, mechanisms and functions. J. Leukoc. Biol. 2004;75:163-189.

    Not in our library10.1189/jlb.0603252

  26. 26.
    Mesenchymal Stem Cell Transition to Tumor-Associated Fibroblasts Contributes to Fibrovascular Network Expansion and Tumor Progression · 2009
    Corrected
  27. 27.

    Delort L., Cholet J., Decombat C., Vermerie M., Dumontet C., Castelli F.A., Fenaille F., Auxenfans C., Rossary A., Caldefie-Chezet F. The Adipose Microenvironment Dysregulates the Mammary Myoepithelial Cells and Could Participate to the Progression of Breast Cancer. Front. Cell Dev. Biol. 2021;8:571948.

    Not in our library10.3389/fcell.2020.571948

  28. 28.

    Hanahan D., Weinberg R.A. Hallmarks of Cancer: The Next Generation. Cell. 2011;144:646-674.

    Not in our library10.1016/j.cell.2011.02.013

  29. 29.

    Kawai T., Autieri M.V., Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am. J. Physiol.-Cell Physiol. 2021;320:C375-C391.

    Not in our library10.1152/ajpcell.00379.2020

  30. 30.

    Singh N., Baby D., Rajguru J., Patil P., Thakkannavar S., Pujari V. Inflammation and cancer. Ann. Afr. Med. 2019;18:121.

    Not in our library10.4103/aam.aam_56_18

  31. 31.

    Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Nature. 2008;454:436-444.

    Not in our library10.1038/nature07205

  32. 32.

    Frankenberger C., Rabe D., Bainer R., Sankarasharma D., Chada K., Krausz T., Gilad Y., Becker L., Rosner M.R. Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages. Cancer Res. 2015;75:4063-4073.

    Not in our library10.1158/0008-5472.can-14-3394

  33. 33.

    Rosenberg S.A. IL-2: The First Effective Immunotherapy for Human Cancer. J. Immunol. 2014;192:5451-5458.

    Not in our library10.4049/jimmunol.1490019

  34. 34.

    Risso G., Blaustein M., Pozzi B., Mammi P., Srebrow A. Akt/PKB: One kinase, many modifications. Biochem. J. 2015;468:203-214.

    Not in our library10.1042/bj20150041

  35. 35.

    Gonzalez-Perez R.R., Xu Y., Guo S., Watters A., Zhou W., Leibovich S.J. Leptin upregulates VEGF in breast cancer via canonic and non-canonical signalling pathways and NFκB/HIF-1α activation. Cell. Signal. 2010;22:1350-1362.

    Not in our library10.1016/j.cellsig.2010.05.003

  36. 36.

    Tartaglia L.A., Dembski M., Weng X., Deng N., Culpepper J., Devos R., Richards G.J., Campfield L.A., Clark F.T., Deeds J., et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263-1271.

    Not in our library10.1016/0092-8674(95)90151-5

  37. 37.

    Halaas J.L., Gajiwala K.S., Maffei M., Cohen S.L., Chait B.T., Rabinowitz D., Lallone R.L., Burley S.K., Friedman J.M. Weight-Reducing Effects of the Plasma Protein Encoded by the obese Gene. Science. 1995;269:543-546.

    Not in our library10.1126/science.7624777

  38. 38.

    Santander A., Lopez-Ocejo O., Casas O., Agostini T., Sanchez L., Lamas-Basulto E., Carrio R., Cleary M., Gonzalez-Perez R., Torroella-Kouri M. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue. Cancers. 2015;7:143-178.

    Not in our library10.3390/cancers7010143

  39. 39.

    Ip W.K.E., Hoshi N., Shouval D.S., Snapper S., Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017;356:513-519.

    Not in our library10.1126/science.aal3535

  40. 40.

    Sánchez-Margalet V., Martín-Romero C., Santos-Alvarez J., Goberna R., Najib S., Gonzalez-Yanes C. Role of leptin as an immunomodulator of blood mononuclear cells: Mechanisms of action. Clin. Exp. Immunol. 2003;133:11-19.

    Not in our library10.1046/j.1365-2249.2003.02190.x

  41. 41.

    Cruceriu D., Baldasici O., Balacescu O., Berindan-Neagoe I. The dual role of tumor necrosis factor-alpha (TNF-α) in breast cancer: Molecular insights and therapeutic approaches. Cell. Oncol. 2020;43:1-18.

    Not in our library10.1007/s13402-019-00489-1

  42. 42.

    Aggarwal B.B., Shishodia S., Takada Y., Jackson-Bernitsas D., Ahn K.S., Sethi G., Ichikawa H., Numerof R., Dinarello C.A., Asadullah K. TNF Blockade: An Inflammatory Issue. Cytokines as Potential Therapeutic Targets for Inflammatory Skin Diseases. 2005;Volume 56:161-186.

    Not in our library10.1007/3-540-37673-9_10

  43. 43.

    Callahan M.K., Williamson P., Schlegel R.A. Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes. Cell Death Differ. 2000;7:645-653.

    Not in our library10.1038/sj.cdd.4400690

  44. 44.

    Hawkes J.E., Yan B.Y., Chan T.C., Krueger J.G. Discovery of the IL-23/IL-17 Signaling Pathway and the Treatment of Psoriasis. J. Immunol. 2018;201:1605-1613.

    Not in our library10.4049/jimmunol.1800013

  45. 45.

    Aggarwal B.B. Signalling pathways of the TNF superfamily: A double-edged sword. Nat. Rev. Immunol. 2003;3:745-756.

    Not in our library10.1038/nri1184

  46. 46.

    Aggarwal B.B., Shishodia S., Ashikawa K., Bharti A.C. The Role of TNF and Its Family Members in Inflammation and Cancer: Lessons from Gene Deletion. Curr. Drug Target-Inflamm. Allergy. 2002;1:327-341.

    Not in our library10.2174/1568010023344571

  47. 47.

    Aggarwal B.B., Takada Y., Platanias L.C. Pro-apototic and Anti-apoptotic Effects of Tumor Necrosis Factor in Tumor Cells. Cytokines and Cancer. 2005;Volume 126:103-127.

    Not in our library10.1007/0-387-24361-5_5

  48. 48.

    Aggarwal B.B. Nuclear factor-κB. Cancer Cell. 2004;6:203-208.

    Not in our library10.1016/j.ccr.2004.09.003

  49. 49.
    Targeting Inflammatory Pathways by Triterpenoids for Prevention and Treatment of Cancer · 2010
    No notice
  50. 50.

    Arendt L.M., McCready J., Keller P.J., Baker D.D., Naber S.P., Seewaldt V., Kuperwasser C. Obesity Promotes Breast Cancer by CCL2-Mediated Macrophage Recruitment and Angiogenesis. Cancer Res. 2013;73:6080-6093.

    Not in our library10.1158/0008-5472.can-13-0926

  51. 51.

    Welte G., Alt E., Devarajan E., Krishnappa S., Jotzu C., Song Y.-H. Interleukin-8 derived from local tissue-resident stromal cells promotes tumor cell invasion. Mol. Carcinog. 2012;51:861-868.

    Not in our library10.1002/mc.20854

  52. 52.

    Coussens L.M., Werb Z. Inflammation and cancer. Nature. 2002;420:860-867.

    Not in our library10.1038/nature01322

  53. 53.

    Ben-Baruch A. The Tumor-Promoting Flow of Cells Into, Within and Out of the Tumor Site: Regulation by the Inflammatory Axis of TNFα and Chemokines. Cancer Microenviron. 2012;5:151-164.

    Not in our library10.1007/s12307-011-0094-3

  54. 54.
    Interleukin-1β and Cancer · 2020
    No notice
  55. 55.

    Kim J.-E., Phan T.X., Nguyen V.H., Dinh-Vu H.-V., Zheng J.H., Yun M., Park S.-G., Hong Y., Choy H.E., Szardenings M., et al. Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1β. Theranostics. 2015;5:1328-1342.

    Not in our library10.7150/thno.11432

  56. 56.

    Li H.-J., Reinhardt F., Herschman H.R., Weinberg R.A. Cancer-Stimulated Mesenchymal Stem Cells Create a Carcinoma Stem Cell Niche via Prostaglandin E2 Signaling. Cancer Discov. 2012;2:840-855.

    Not in our library10.1158/2159-8290.cd-12-0101

  57. 57.

    Coffelt S.B., Kersten K., Doornebal C.W., Weiden J., Vrijland K., Hau C.-S., Verstegen N.J.M., Ciampricotti M., Hawinkels L.J.A.C., Jonkers J., et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature. 2015;522:345-348.

    Not in our library10.1038/nature14282

  58. 58.

    Franco-Barraza J., Valdivia-Silva J.E., Zamudio-Meza H., Castillo A., García-Zepeda E.A., Benítez-Bribiesca L., Meza I. Actin Cytoskeleton Participation in the Onset of IL-1β Induction of an Invasive Mesenchymal-like Phenotype in Epithelial MCF-7 Cells. Arch. Med. Res. 2010;41:170-181.

    Not in our library10.1016/j.arcmed.2010.04.010

  59. 59.

    Ma L., Lan F., Zheng Z., Xie F., Wang L., Liu W., Han J., Zheng F., Xie Y., Huang Q. Epidermal growth factor (EGF) and interleukin (IL)-1β synergistically promote ERK1/2-mediated invasive breast ductal cancer cell migration and invasion. Mol. Cancer. 2012;11:79.

    Not in our library10.1186/1476-4598-11-79

  60. 60.

    Hou Z., Falcone D.J., Subbaramaiah K., Dannenberg A.J. Macrophages induce COX-2 expression in breast cancer cells: Role of IL-1β autoamplification. Carcinogenesis. 2011;32:695-702.

    Not in our library10.1093/carcin/bgr027

  61. 61.

    Reed J.R., Leon R.P., Hall M.K., Schwertfeger K.L. Interleukin-1beta and fibroblast growth factor receptor 1 cooperate to induce cyclooxygenase-2 during early mammary tumourigenesis. Breast Cancer Res. 2009;11:R21.

    Not in our library10.1186/bcr2246

  62. 62.

    Cytokine Tutorial.

    Not in our library

  63. 63.

    Wellenstein M.D., Coffelt S.B., Duits D.E.M., van Miltenburg M.H., Slagter M., de Rink I., Henneman L., Kas S.M., Prekovic S., Hau C.-S., et al. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature. 2019;572:538-542.

    Not in our library10.1038/s41586-019-1450-6

  64. 64.

    Huang J., Lan X., Wang T., Lu H., Cao M., Yan S., Cui Y., Jia D., Cai L., Xing Y. Targeting the IL-1β/EHD1/TUBB3 axis overcomes resistance to EGFR-TKI in NSCLC. Oncogene. 2020;39:1739-1755.

    Not in our library10.1038/s41388-019-1099-5

  65. 65.

    Jiménez-Garduño A.M., Mendoza-Rodríguez M.G., Urrutia-Cabrera D., Domínguez-Robles M.C., Pérez-Yépez E.A., Ayala-Sumuano J.T., Meza I. IL-1β induced methylation of the estrogen receptor ERα gene correlates with EMT and chemoresistance in breast cancer cells. Biochem. Biophys. Res. Commun. 2017;490:780-785.

    Not in our library10.1016/j.bbrc.2017.06.117

  66. 66.

    Zhou J., Tulotta C., Ottewell P.D. IL-1β in breast cancer bone metastasis. Expert Rev. Mol. Med. 2022;24:e11.

    Not in our library10.1017/erm.2022.4

  67. 67.

    Carmi Y., Voronov E., Dotan S., Lahat N., Rahat M.A., Fogel M., Huszar M., White M.R., Dinarello C.A., Apte R.N. The Role of Macrophage-Derived IL-1 in Induction and Maintenance of Angiogenesis. J. Immunol. 2009;183:4705-4714.

    Not in our library10.4049/jimmunol.0901511

  68. 68.

    Carmi Y., Dotan S., Rider P., Kaplanov I., White M.R., Baron R., Abutbul S., Huszar M., Dinarello C.A., Apte R.N., et al. The Role of IL-1β in the Early Tumor Cell–Induced Angiogenic Response. J. Immunol. 2013;190:3500-3509.

    Not in our library10.4049/jimmunol.1202769

  69. 69.

    Schmid M.C., Avraamides C.J., Foubert P., Shaked Y., Kang S.W., Kerbel R.S., Varner J.A. Combined Blockade of Integrin-α4β1 Plus Cytokines SDF-1α or IL-1β Potently Inhibits Tumor Inflammation and Growth. Cancer Res. 2011;71:6965-6975.

    Not in our library10.1158/0008-5472.can-11-0588

  70. 70.

    Naldini A., Filippi I., Miglietta D., Moschetta M., Giavazzi R., Carraro F. Interleukin-1β regulates the migratory potential of MDAMB231 breast cancer cells through the hypoxia-inducible factor-1α. Eur. J. Cancer. 2010;46:3400-3408.

    Not in our library10.1016/j.ejca.2010.07.044

  71. 71.

    Solís-Martínez R., Cancino-Marentes M., Hernández-Flores G., Ortiz-Lazareno P., Mandujano-Álvarez G., Cruz-Gálvez C., Sierra-Díaz E., Rodríguez-Padilla C., Jave-Suárez L.F., Aguilar-Lemarroy A., et al. Regulation of immunophenotype modulation of monocytes-macrophages from M1 into M2 by prostate cancer cell-culture supernatant via transcription factor STAT3. Immunol. Lett. 2018;196:140-148.

    Not in our library10.1016/j.imlet.2018.02.009

  72. 72.

    Fu X.-L., Duan W., Su C.-Y., Mao F.-Y., Lv Y.-P., Teng Y.-S., Yu P.-W., Zhuang Y., Zhao Y.-L. Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression. Cancer Immunol. Immunother. 2017;66:1597-1608.

    Not in our library10.1007/s00262-017-2052-5

  73. 73.

    Grivennikov S., Karin E., Terzic J., Mucida D., Yu G.-Y., Vallabhapurapu S., Scheller J., Rose-John S., Cheroutre H., Eckmann L., et al. IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer. Cancer Cell. 2009;15:103-113.

    Not in our library10.1016/j.ccr.2009.01.001

  74. 74.

    Mitchem J.B., Brennan D.J., Knolhoff B.L., Belt B.A., Zhu Y., Sanford D.E., Belaygorod L., Carpenter D., Collins L., Piwnica-Worms D., et al. Targeting Tumor-Infiltrating Macrophages Decreases Tumor-Initiating Cells, Relieves Immunosuppression, and Improves Chemotherapeutic Responses. Cancer Res. 2013;73:1128-1141.

    Not in our library10.1158/0008-5472.can-12-2731

  75. 75.

    Ibrahim M.M. Subcutaneous and visceral adipose tissue: Structural and functional differences. Obes. Rev. 2010;11:11-18.

    Not in our library10.1111/j.1467-789x.2009.00623.x

  76. 76.

    Vgontzas A.N., Papanicolaou D.A., Bixler E.O., Kales A., Tyson K., Chrousos G.P. Elevation of Plasma Cytokines in Disorders of Excessive Daytime Sleepiness: Role of Sleep Disturbance and Obesity. J. Clin. Endocrinol. Metab. 1997;82:1313-1316.

    Not in our library10.1210/jcem.82.5.3950

  77. 77.

    Zhao X., Sun X., Gao F., Luo J., Sun Z. Effects of ulinastatin and docataxel on breast tumor growth and expression of IL-6, IL-8, and TNF-α. J. Exp. Clin. Cancer Res. 2011;30:22.

    Not in our library10.1186/1756-9966-30-22

  78. 78.

    Kishimoto T., Hirano T. Molecular Regulation of B Lymphocyte Response. Annu. Rev. Immunol. 1988;6:485-512.

    Not in our library10.1146/annurev.iy.06.040188.002413

  79. 79.

    Takenawa J., Kaneko Y., Fukumoto M., Fukatsu A., Hirano T., Fukuyama H., Nakayama H., Fujita J., Yoshida O. Enhanced Expression of Interleukin-6 in Primary Human Renal Cell Carcinomas. J. Natl. Cancer Inst. 1991;83:1668-1672.

    Not in our library10.1093/jnci/83.22.1668

  80. 80.

    Xie T., Wei D., Liu M., Gao A.C., Ali-Osman F., Sawaya R., Huang S. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene. 2004;23:3550-3560.

    Not in our library10.1038/sj.onc.1207383

  81. 81.

    Goswami S., Gupta A., Sharma S.K. Interleukin-6-Mediated Autocrine Growth Promotion in Human Glioblastoma Multiforme Cell Line U87MG. J. Neurochem. 2002;71:1837-1845.

    Not in our library10.1046/j.1471-4159.1998.71051837.x

  82. 82.

    Bromberg J., Wang T.C. Inflammation and Cancer: IL-6 and STAT3 Complete the Link. Cancer Cell. 2009;15:79-80.

    Not in our library10.1016/j.ccr.2009.01.009

  83. 83.

    Barbieri I., Pensa S., Pannellini T., Quaglino E., Maritano D., Demaria M., Voster A., Turkson J., Cavallo F., Watson C.J., et al. Constitutively Active Stat3 Enhances Neu-Mediated Migration and Metastasis in Mammary Tumors via Upregulation of Cten. Cancer Res. 2010;70:2558-2567.

    Not in our library10.1158/0008-5472.can-09-2840

  84. 84.

    Bromberg J., Darnell J.E. The role of STATs in transcriptional control and their impact on cellular function. Oncogene. 2000;19:2468-2473.

    Not in our library10.1038/sj.onc.1203476

  85. 85.

    Stark G.R., Darnell J.E. The JAK-STAT Pathway at Twenty. Immunity. 2012;36:503-514.

    Not in our library10.1016/j.immuni.2012.03.013

  86. 86.

    Demaria M., Misale S., Giorgi C., Miano V., Camporeale A., Campisi J., Pinton P., Poli V. STAT3 can serve as a hit in the process of malignant transformation of primary cells. Cell Death Differ. 2012;19:1390-1397.

    Not in our library10.1038/cdd.2012.20

  87. 87.

    Knüpfer H., Preiß R. Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res. Treat. 2007;102:129-135.

    Not in our library10.1007/s10549-006-9328-3

  88. 88.
    Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients · 2003
    No notice
  89. 89.

    Arihiro K., Oda H., Kaneko M., Inai K. Cytokines facilitate chemotactic motility of breast carcinoma cells. Breast Cancer. 2000;7:221-230.

    Not in our library10.1007/bf02967464

  90. 90.

    Sehgal P.B., Tamm I., Goldberg I.D. Interleukin-6 enhances motility of breast carcinoma cells. Cell Motility Factors. 1991;Volume 59:178-193.

    Not in our library10.1007/978-3-0348-7494-6_12

  91. 91.

    Park S.-J., Nakagawa T., Kitamura H., Atsumi T., Kamon H., Sawa S., Kamimura D., Ueda N., Iwakura Y., Ishihara K., et al. IL-6 Regulates In Vivo Dendritic Cell Differentiation through STAT3 Activation. J. Immunol. 2004;173:3844-3854.

    Not in our library10.4049/jimmunol.173.6.3844

  92. 92.

    Heink S., Yogev N., Garbers C., Herwerth M., Aly L., Gasperi C., Husterer V., Croxford A.L., Möller-Hackbarth K., Bartsch H.S., et al. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat. Immunol. 2017;18:74-85.

    Not in our library10.1038/ni.3632

  93. 93.

    Chomarat P., Banchereau J., Davoust J., Karolina Palucka A. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat. Immunol. 2000;1:510-514.

    Not in our library10.1038/82763

  94. 94.

    Dejean A.S., Beisner D.R., Ch’en I.L., Kerdiles Y.M., Babour A., Arden K.C., Castrillon D.H., DePinho R.A., Hedrick S.M. Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells. Nat. Immunol. 2009;10:504-513.

    Not in our library10.1038/ni.1729

  95. 95.

    Chen Q., Fisher D.T., Kucinska S.A., Wang W.-C., Evans S.S. Dynamic control of lymphocyte trafficking by fever-range thermal stress. Cancer Immunol. Immunother. 2006;55:299-311.

    Not in our library10.1007/s00262-005-0022-9

  96. 96.

    Fu X.-T., Dai Z., Song K., Zhang Z.-J., Zhou Z.-J., Zhou S.-L., Zhao Y.-M., Xiao Y.-S., Sun Q.-M., Ding Z.-B., et al. Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2/STAT3/Snail pathway. Int. J. Oncol. 2015;46:587-596.

    Not in our library10.3892/ijo.2014.2761

  97. 97.

    Chen S., Lian G., Li J., Zhang Q., Zeng L., Yang K., Huang C., Li Y., Chen Y., Huang K. Tumor-driven like macrophages induced by conditioned media from pancreatic ductal adenocarcinoma promote tumor metastasis via secreting IL-8. Cancer Med. 2018;7:5679-5690.

    Not in our library10.1002/cam4.1824

  98. 98.

    Peveri P., Walz A., Dewald B., Baggiolini M. A novel neutrophil-activating factor produced by human mononuclear phagocytes. J. Exp. Med. 1988;167:1547-1559.

    Not in our library10.1084/jem.167.5.1547

  99. 99.

    Wanninger J., Neumeier M., Weigert J., Bauer S., Weiss T.S., Schäffler A., Krempl C., Bleyl C., Aslanidis C., Schölmerich J., et al. Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-κB, and STAT3 signaling pathways. Am. J. Physiol.-Gastrointest. Liver Physiol. 2009;297:G611-G618.

    Not in our library10.1152/ajpgi.90644.2008

  100. 100.

    Kwon O.J., Au B.T., Collins P.D., Adcock I.M., Mak J.C., Robbins R.R., Chung K.F., Barnes P.J. Tumor necrosis factor-induced interleukin-8 expression in cultured human airway epithelial cells. Am. J. Physiol.-Lung Cell. Mol. Physiol. 1994;267:L398-L405.

    Not in our library10.1152/ajplung.1994.267.4.l398

  101. 101.

    Vijay V., Miller R., Vue G.S., Pezeshkian M.B., Maywood M., Ast A.M., Drusbosky L.M., Pompeu Y., Salgado A.D., Lipten S.D., et al. Interleukin-8 blockade prevents activated endothelial cell mediated proliferation and chemoresistance of acute myeloid leukemia. Leuk. Res. 2019;84:106180.

    Not in our library10.1016/j.leukres.2019.106180

  102. 102.

    Chen Y., McAndrews K.M., Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat. Rev. Clin. Oncol. 2021;18:792-804.

    Not in our library10.1038/s41571-021-00546-5

  103. 103.

    Knall C., Worthen G.S., Buhl A.M., Johnson G.L. IL-8 Signal Transduction in Human Neutrophils. Ann. N. Y. Acad. Sci. 1995;766:288-291.

    Not in our library10.1111/j.1749-6632.1995.tb26679.x

  104. 104.

    Glynn P.C., Henney E., Hall I.P. The Selective CXCR2 Antagonist SB272844 Blocks Interleukin-8 and Growth-related Oncogene-α-mediated Inhibition of Spontaneous Neutrophil Apoptosis. Pulm. Pharmacol. Ther. 2002;15:103-110.

    Not in our library10.1006/pupt.2001.0323

  105. 105.

    Statement of Retraction: Significance of the IL-8 pathway for immunotherapy. Hum. Vaccines Immunother. 2022;18:2052703.

    Not in our library10.1080/21645515.2022.2052703

  106. 106.
    Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases · 1997
    Not checked
  107. 107.

    Murphy C., McGurk M., Pettigrew J., Santinelli A., Mazzucchelli R., Johnston P.G., Montironi R., Waugh D.J.J. Nonapical and Cytoplasmic Expression of Interleukin-8, CXCR1, and CXCR2 Correlates with Cell Proliferation and Microvessel Density in Prostate Cancer. Clin. Cancer Res. 2005;11:4117-4127.

    Not in our library10.1158/1078-0432.ccr-04-1518

  108. 108.

    Waugh D.J.J., Wilson C. The Interleukin-8 Pathway in Cancer. Clin. Cancer Res. 2008;14:6735-6741.

    Not in our library10.1158/1078-0432.ccr-07-4843

  109. 109.

    Cohenhillel E., Yron I., Meshel T., Soria G., Attal H., Benbaruch A. CXCL8-induced FAK phosphorylation via CXCR1 and CXCR2: Cytoskeleton- and integrin-related mechanisms converge with FAK regulatory pathways in a receptor-specific manner. Cytokine. 2006;33:1-16.

    Not in our library10.1016/j.cyto.2005.11.006

  110. 110.

    Ning Y., Cui Y., Li X., Cao X., Chen A., Xu C., Cao J., Luo X. Co-culture of ovarian cancer stem-like cells with macrophages induced SKOV3 cells stemness via IL-8/STAT3 signaling. Biomed. Pharmacother. 2018;103:262-271.

    Not in our library10.1016/j.biopha.2018.04.022

  111. 111.

    Sparmann A., Bar-Sagi D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell. 2004;6:447-458.

    Not in our library10.1016/j.ccr.2004.09.028

  112. 112.

    Roskoski R. ERK1/2 MAP kinases: Structure, function, and regulation. Pharmacol. Res. 2012;66:105-143.

    Not in our library10.1016/j.phrs.2012.04.005

  113. 113.

    Omi K., Matsuo Y., Ueda G., Aoyama Y., Kato T., Hayashi Y., Imafuji H., Saito K., Tsuboi K., Morimoto M., et al. Escin inhibits angiogenesis by suppressing interleukin-8 and vascular endothelial growth factor production by blocking nuclear factor-κB activation in pancreatic cancer cell lines. Oncol. Rep. 2021;45:55.

    Not in our library10.3892/or.2021.8006

  114. 114.

    Cheng J.Q., Lindsley C.W., Cheng G.Z., Yang H., Nicosia S.V. The Akt/PKB pathway: Molecular target for cancer drug discovery. Oncogene. 2005;24:7482-7492.

    Not in our library10.1038/sj.onc.1209088

  115. 115.

    Siesser P.M.F., Hanks S.K. The Signaling and Biological Implications of FAK Overexpression in Cancer. Clin. Cancer Res. 2006;12:3233-3237.

    Not in our library10.1158/1078-0432.ccr-06-0456

  116. 116.
    Genistein inhibits stemness of SKOV3 cells induced by macrophages co-cultured with ovarian cancer stem-like cells through IL-8/STAT3 axis · 2019
    Not checked
  117. 117.
    IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma · 2019
    No notice
  118. 118.

    Xiao P., Long X., Zhang L., Ye Y., Guo J., Liu P., Zhang R., Ning J., Yu W., Wei F., et al. Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of Tumor-Associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells. OncoImmunology. 2018;7:e1440166.

    Not in our library10.1080/2162402x.2018.1440166

  119. 119.

    Yang M., Zhang G., Wang Y., He M., Xu Q., Lu J., Liu H., Xu C. Tumour-associated neutrophils orchestrate intratumoural IL-8-driven immune evasion through Jagged2 activation in ovarian cancer. Br. J. Cancer. 2020;123:1404-1416.

    Not in our library10.1038/s41416-020-1026-0

  120. 120.

    Samie A., Dzhivhuho G.A., Nangammbi T.C. Distribution of CXCR2 +1208 T/C gene polymorphisms in relation to opportunistic infections among HIV-infected patients in Limpopo Province, South Africa. Genet. Mol. Res. 2014;13:7470-7479.

    Not in our library10.4238/2014.september.12.13

  121. 121.

    Ignacio A., Breda C.N.S., Camara N.O.S. Innate lymphoid cells in tissue homeostasis and diseases. World J. Hepatol. 2017;9:979.

    Not in our library10.4254/wjh.v9.i23.979

  122. 122.

    Tian Z., van Velkinburgh J.C., Wu Y., Ni B. Innate lymphoid cells involve in tumorigenesis: Effects of ILCs on tumorigenesis. Int. J. Cancer. 2016;138:22-29.

    Not in our library10.1002/ijc.29443

  123. 123.

    Tamassia N., Arruda-Silva F., Wright H.L., Moots R.J., Gardiman E., Bianchetto-Aguilera F., Gasperini S., Capone M., Maggi L., Annunziato F., et al. Human neutrophils activated via TLR8 promote Th17 polarization through IL-23. J. Leukoc. Biol. 2019;105:1155-1165.

    Not in our library10.1002/jlb.ma0818-308r

  124. 124.

    Parham C., Chirica M., Timans J., Vaisberg E., Travis M., Cheung J., Pflanz S., Zhang R., Singh K.P., Vega F., et al. A Receptor for the Heterodimeric Cytokine IL-23 Is Composed of IL-12Rβ1 and a Novel Cytokine Receptor Subunit, IL-23R. J. Immunol. 2002;168:5699-5708.

    Not in our library10.4049/jimmunol.168.11.5699

  125. 125.

    Zhou L., Ivanov I.I., Spolski R., Min R., Shenderov K., Egawa T., Levy D.E., Leonard W.J., Littman D.R. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 2007;8:967-974.

    Not in our library10.1038/ni1488

  126. 126.

    Nie W., Yu T., Sang Y., Gao X. Tumor-promoting effect of IL-23 in mammary cancer mediated by infiltration of M2 macrophages and neutrophils in tumor microenvironment. Biochem. Biophys. Res. Commun. 2017;482:1400-1406.

    Not in our library10.1016/j.bbrc.2016.12.048

  127. 127.

    Yan J., Smyth M.J., Teng M.W.L. Interleukin (IL)-12 and IL-23 and Their Conflicting Roles in Cancer. Cold Spring Harb. Perspect. Biol. 2018;10:a028530.

    Not in our library10.1101/cshperspect.a028530

  128. 128.

    Du J.-W., Xu K.-Y., Fang L.-Y., Qi X.-L. Interleukin-17, produced by lymphocytes, promotes tumor growth and angiogenesis in a mouse model of breast cancer. Mol. Med. Rep. 2012;6:1099-1102.

    Not in our library10.3892/mmr.2012.1036

  129. 129.

    Langowski J.L., Zhang X., Wu L., Mattson J.D., Chen T., Smith K., Basham B., McClanahan T., Kastelein R.A., Oft M. IL-23 promotes tumour incidence and growth. Nature. 2006;442:461-465.

    Not in our library10.1038/nature04808

  130. 130.

    Gaffen S.L., Jain R., Garg A.V., Cua D.J. The IL-23–IL-17 immune axis: From mechanisms to therapeutic testing. Nat. Rev. Immunol. 2014;14:585-600.

    Not in our library10.1038/nri3707

  131. 131.

    Park H., Li Z., Yang X.O., Chang S.H., Nurieva R., Wang Y.-H., Wang Y., Hood L., Zhu Z., Tian Q., et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 2005;6:1133-1141.

    Not in our library10.1038/ni1261

  132. 132.

    Ouyang W., Kolls J.K., Zheng Y. The Biological Functions of T Helper 17 Cell Effector Cytokines in Inflammation. Immunity. 2008;28:454-467.

    Not in our library10.1016/j.immuni.2008.03.004

  133. 133.

    Wang L., Yi T., Kortylewski M., Pardoll D.M., Zeng D., Yu H. IL-17 can promote tumor growth through an IL-6–Stat3 signaling pathway. J. Exp. Med. 2009;206:1457-1464.

    Not in our library10.1084/jem.20090207

  134. 134.
    IL-17 expression by breast-cancer-associated macrophages: IL-17 promotes invasiveness of breast cancer cell lines · 2008
    No notice
  135. 135.

    Tait Wojno E.D., Hunter C.A., Stumhofer J.S. The Immunobiology of the Interleukin-12 Family: Room for Discovery. Immunity. 2019;50:851-870.

    Not in our library10.1016/j.immuni.2019.03.011

  136. 136.

    Liao W., Lin J.-X., Leonard W.J. IL-2 family cytokines: New insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr. Opin. Immunol. 2011;23:598-604.

    Not in our library10.1016/j.coi.2011.08.003

  137. 137.

    Yui M.A., Sharp L.L., Havran W.L., Rothenberg E.V. Preferential Activation of an IL-2 Regulatory Sequence Transgene in TCRγδ and NKT Cells: Subset-Specific Differences in IL-2 Regulation. J. Immunol. 2004;172:4691-4699.

    Not in our library10.4049/jimmunol.172.8.4691

  138. 138.

    Granucci F. NEW EMBO MEMBER’S REVIEW: Dendritic cell regulation of immune responses: A new role for interleukin 2 at the intersection of innate and adaptive immunity. EMBO J. 2003;22:2546-2551.

    Not in our library10.1093/emboj/cdg261

  139. 139.

    Henney C.S., Kuribayashi K., Kern D.E., Gillis S. Interleukin-2 augments natural killer cell activity. Nature. 1981;291:335-338.

    Not in our library10.1038/291335a0

  140. 140.

    Blackman M.A., Tigges M.A., Minie M.E., Koshland M.E. A model system for peptide hormone action in differentiation: Interleukin 2 induces a B lymphoma to transcribe the J chain gene. Cell. 1986;47:609-617.

    Not in our library10.1016/0092-8674(86)90625-2

  141. 141.

    Rochman Y., Spolski R., Leonard W.J. New insights into the regulation of T cells by γc family cytokines. Nat. Rev. Immunol. 2009;9:480-490.

    Not in our library10.1038/nri2580

  142. 142.

    Wei S., Blanchard D.K., Liu J.H., Leonard W.J., Djeu J.Y. Activation of tumor necrosis factor-alpha production from human neutrophils by IL-2 via IL-2-R beta. J. Immunol. 1993;150:1979.

    Not in our library10.4049/jimmunol.150.5.1979

  143. 143.

    Reichert T.E., Kashii Y., Stanson J., Zeevi A., Whiteside T.L. The role of endogenous interleukin-2 in proliferation of human carcinoma cell lines. Br. J. Cancer. 1999;81:822-831.

    Not in our library10.1038/sj.bjc.6690770

  144. 144.

    Rudensky A.Y. Regulatory T cells and Foxp3: Regulatory T cells and Foxp3. Immunol. Rev. 2011;241:260-268.

    Not in our library10.1111/j.1600-065x.2011.01018.x

  145. 145.

    Brisslert M., Bokarewa M., Larsson P., Wing K., Collins L.V., Tarkowski A. Phenotypic and functional characterization of human CD25+ B cells. Immunology. 2006;117:548-557.

    Not in our library10.1111/j.1365-2567.2006.02331.x

  146. 146.

    Krieg C., Létourneau S., Pantaleo G., Boyman O. Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc. Natl. Acad. Sci. USA. 2010;107:11906-11911.

    Not in our library10.1073/pnas.1002569107

  147. 147.

    Malek T.R., Castro I. Interleukin-2 Receptor Signaling: At the Interface between Tolerance and Immunity. Immunity. 2010;33:153-165.

    Not in our library10.1016/j.immuni.2010.08.004

  148. 148.

    Littman D.R., Rudensky A.Y. Th17 and Regulatory T Cells in Mediating and Restraining Inflammation. Cell. 2010;140:845-858.

    Not in our library10.1016/j.cell.2010.02.021

  149. 149.

    Leung D.T.M., Morefield S., Willerford D.M. Regulation of Lymphoid Homeostasis by IL-2 Receptor Signals In Vivo. J. Immunol. 2000;164:3527-3534.

    Not in our library10.4049/jimmunol.164.7.3527

  150. 150.

    Liao W., Lin J.-X., Wang L., Li P., Leonard W.J. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat. Immunol. 2011;12:551-559.

    Not in our library10.1038/ni.2030

  151. 151.

    Liao W., Schones D.E., Oh J., Cui Y., Cui K., Roh T.-Y., Zhao K., Leonard W.J. Priming for T helper type 2 differentiation by interleukin 2–mediated induction of interleukin 4 receptor α-chain expression. Nat. Immunol. 2008;9:1288-1296.

    Not in our library10.1038/ni.1656

  152. 152.

    Friedmann M.C., Migone T.S., Russell S.M., Leonard W.J. Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation. Proc. Natl. Acad. Sci. USA. 1996;93:2077-2082.

    Not in our library10.1073/pnas.93.5.2077

  153. 153.

    Lin J.-X., Migone T.-S., Tseng M., Friedmann M., Weatherbee J.A., Zhou L., Yamauchi A., Bloom E.T., Mietz J., John S., et al. The role of shared receptor motifs and common stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity. 1995;2:331-339.

    Not in our library10.1016/1074-7613(95)90141-8

  154. 154.

    Abbas A.K., Murphy K.M., Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383:787-793.

    Not in our library10.1038/383787a0

  155. 155.
    Roles of IFN-γ in tumor progression and regression: a review · 2020
    No notice
  156. 156.

    Cua D.J., Tato C.M. Innate IL-17-producing cells: The sentinels of the immune system. Nat. Rev. Immunol. 2010;10:479-489.

    Not in our library10.1038/nri2800

  157. 157.

    Schoenborn J.R., Wilson C.B. Regulation of Interferon-γ During Innate and Adaptive Immune Responses. Advances in Immunology. 2007;Volume 96:41-101.

    Not in our library10.1016/s0065-2776(07)96002-2

  158. 158.

    Olson M.R., Russ B.E., Doherty P.C., Turner S.J. The role of epigenetics in the acquisition and maintenance of effector function in virus-specific CD8 T cells. IUBMB Life. 2010;62:519-526.

    Not in our library10.1002/iub.351

  159. 159.

    Burke J.D., Young H.A. IFN-γ: A cytokine at the right time, is in the right place. Semin. Immunol. 2019;43:101280.

    Not in our library10.1016/j.smim.2019.05.002

  160. 160.

    Thieu V.T., Yu Q., Chang H.-C., Yeh N., Nguyen E.T., Sehra S., Kaplan M.H. Signal Transducer and Activator of Transcription 4 Is Required for the Transcription Factor T-bet to Promote T Helper 1 Cell-Fate Determination. Immunity. 2008;29:679-690.

    Not in our library10.1016/j.immuni.2008.08.017

  161. 161.

    Poggi A., Giuliani M. Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment. Vaccines. 2016;4:41.

    Not in our library10.3390/vaccines4040041

  162. 162.

    Garcia-Diaz A., Shin D.S., Moreno B.H., Saco J., Escuin-Ordinas H., Rodriguez G.A., Zaretsky J.M., Sun L., Hugo W., Wang X., et al. Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression. Cell Rep. 2017;19:1189-1201.

    Not in our library10.1016/j.celrep.2017.04.031

  163. 163.

    Gough D.J., Levy D.E., Johnstone R.W., Clarke C.J. IFNγ signaling—Does it mean JAK–STAT? Cytokine Growth Factor Rev. 2008;19:383-394.

    Not in our library10.1016/j.cytogfr.2008.08.004

  164. 164.

    Wang L., Zhao Y., Liu Y., Akiyama K., Chen C., Qu C., Jin Y., Shi S. IFN-γ and TNF-α Synergistically Induce Mesenchymal Stem Cell Impairment and Tumorigenesis via NFκB Signaling. Stem Cells. 2013;31:1383-1395.

    Not in our library10.1002/stem.1388

  165. 165.

    Teixeira L.K., Fonseca B.P., Barboza B.A., Viola J.P. The role of interferon-gamma on immune and allergic responses. Mem. Inst. Oswaldo Cruz. 2005;100:137-144.

    Not in our library10.1590/s0074-02762005000900024

  166. 166.

    Shtrichman R., Samuel C.E. The role of gamma interferon in antimicrobial immunity. Curr. Opin. Microbiol. 2001;4:251-259.

    Not in our library10.1016/s1369-5274(00)00199-5

  167. 167.

    Rocha V.Z., Folco E.J., Sukhova G., Shimizu K., Gotsman I., Vernon A.H., Libby P. Interferon-γ, a Th1 Cytokine, Regulates Fat Inflammation: A Role for Adaptive Immunity in Obesity. Circ. Res. 2008;103:467-476.

    Not in our library10.1161/circresaha.108.177105

  168. 168.

    Lees J.R. Interferon gamma in autoimmunity: A complicated player on a complex stage. Cytokine. 2015;74:18-26.

    Not in our library10.1016/j.cyto.2014.10.014

  169. 169.

    Ivashkiv L.B. IFNγ: Signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat. Rev. Immunol. 2018;18:545-558.

    Not in our library10.1038/s41577-018-0029-z

  170. 170.

    Konjević G.M., Vuletić A.M., Mirjačić Martinović K.M., Larsen A.K., Jurišić V.B. The role of cytokines in the regulation of NK cells in the tumor environment. Cytokine. 2019;117:30-40.

    Not in our library10.1016/j.cyto.2019.02.001

  171. 171.
    CD4 + T Cells: Differentiation and Functions · 2012
    No notice
  172. 172.
    Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity · 2017
    No notice
  173. 173.

    Panduro M., Benoist C., Mathis D. T reg cells limit IFN-γ production to control macrophage accrual and phenotype during skeletal muscle regeneration. Proc. Natl. Acad. Sci. USA. 2018;115:E2585-E2593.

    Not in our library10.1073/pnas.1800618115

  174. 174.

    Chen H.-C., Chou A.S.-B., Liu Y.-C., Hsieh C.-H., Kang C.-C., Pang S.-T., Yeh C.-T., Liu H.-P., Liao S.-K. Induction of metastatic cancer stem cells from the NK/LAK-resistant floating, but not adherent, subset of the UP-LN1 carcinoma cell line by IFN-γ. Lab. Investig. 2011;91:1502-1513.

    Not in our library10.1038/labinvest.2011.91

  175. 175.

    Lo U.-G., Pong R.-C., Yang D., Gandee L., Hernandez E., Dang A., Lin C.-J., Santoyo J., Ma S., Sonavane R., et al. IFNγ-Induced IFIT5 Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer via miRNA Processing. Cancer Res. 2019;79:1098-1112.

    Not in our library10.1158/0008-5472.can-18-2207

  176. 176.

    Berner V., Liu H., Zhou Q., Alderson K.L., Sun K., Weiss J.M., Back T.C., Longo D.L., Blazar B.R., Wiltrout R.H., et al. IFN-γ mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy. Nat. Med. 2007;13:354-360.

    Not in our library10.1038/nm1554

  177. 177.

    Sharma P., Hu-Lieskovan S., Wargo J.A., Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017;168:707-723.

    Not in our library10.1016/j.cell.2017.01.017

  178. 178.

    Allan S.E., Broady R., Gregori S., Himmel M.E., Locke N., Roncarolo M.G., Bacchetta R., Levings M.K. CD4 + T-regulatory cells: Toward therapy for human diseases. Immunol. Rev. 2008;223:391-421.

    Not in our library10.1111/j.1600-065x.2008.00634.x

  179. 179.

    O’Garra A., Vieira P. TH1 cells control themselves by producing interleukin-10. Nat. Rev. Immunol. 2007;7:425-428.

    Not in our library10.1038/nri2097

  180. 180.

    Fillatreau S., Gray D., Anderton S.M. Not always the bad guys: B cells as regulators of autoimmune pathology. Nat. Rev. Immunol. 2008;8:391-397.

    Not in our library10.1038/nri2315

  181. 181.

    Mast Cell Homeostasis: A Fundamental Aspect of Allergic Disease.

    Not in our library

  182. 182.

    Moore K.W., de Waal Malefyt R., Coffman R.L., O’Garra A. Interleukin-10 and the Interleukin-10 Receptor. Annu. Rev. Immunol. 2001;19:683-765.

    Not in our library10.1146/annurev.immunol.19.1.683

  183. 183.

    Williams L.M., Ricchetti G., Sarma U., Smallie T., Foxwell B.M.J. Interleukin-10 suppression of myeloid cell activation—A continuing puzzle. Immunology. 2004;113:281-292.

    Not in our library10.1111/j.1365-2567.2004.01988.x

  184. 184.

    Dillon S. Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. J. Clin. Investig. 2006;116:916-928.

    Not in our library10.1172/jci27203

  185. 185.

    Grimbaldeston M.A., Nakae S., Kalesnikoff J., Tsai M., Galli S.J. Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nat. Immunol. 2007;8:1095-1104.

    Not in our library10.1038/ni1503

  186. 186.

    Akdis C.A., Blaser K. Mechanisms of interleukin-10-mediated immune suppression. Immunology. 2001;103:131-136.

    Not in our library10.1046/j.1365-2567.2001.01235.x

  187. 187.

    Cai G., Kastelein R.A., Hunter C.A. IL-10 enhances NK cell proliferation, cytotoxicity and production of IFN-γ when combined with IL-18. Eur. J. Immunol. 1999;29:2658-2665.

    Not in our library10.1002/(sici)1521-4141(199909)29:09<2658::aid-immu2658>3.0.co;2-g

  188. 188.

    de Waal Malefyt R., Haanen J., Spits H., Roncarolo M.G., te Velde A., Figdor C., Johnson K., Kastelein R., Yssel H., de Vries J.E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J. Exp. Med. 1991;174:915-924.

    Not in our library10.1084/jem.174.4.915

  189. 189.

    Joss A., Akdis M., Faith A., Blaser K., Akdis C.A. IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway. Eur. J. Immunol. 2000;30:1683-1690.

    Not in our library10.1002/1521-4141(200006)30:6<1683::aid-immu1683>3.0.co;2-a

  190. 190.
    Phenotype Switching in Melanoma: Implications for Progression and Therapy · 2015
    No notice
  191. 191.

    Llanes-Fernández L., Álvarez-Goyanes R.I., Arango-Prado M.D.C., Alcocer-González J.M., Mojarrieta J.C., Pérez X.E., López M.O., Odio S.F., Camacho-Rodríguez R., Guerra-Yi M.E., et al. Relationship between IL-10 and tumor markers in breast cancer patients. Breast. 2006;15:482-489.

    Not in our library10.1016/j.breast.2005.09.012

  192. 192.

    Adris S.K., Klein S., Jasnis M.A., Chuluyan E., Ledda M.F., Bravo A.I., Carbone C., Chernajovsky Y., Podhajcer O.L. IL-10 expression by CT26 colon carcinoma cells inhibits their malignant phenotype and induces a T cell-mediated tumor rejection in the context of a systemic Th2 response. Gene Ther. 1999;6:1705-1712.

    Not in our library10.1038/sj.gt.3301012

  193. 193.

    Considine R.V., Sinha M.K., Heiman M.L., Kriauciunas A., Stephens T.W., Nyce M.R., Ohannesian J.P., Marco C.C., McKee L.J., Bauer T.L., et al. Serum Immunoreactive-Leptin Concentrations in Normal-Weight and Obese Humans. N. Engl. J. Med. 1996;334:292-295.

    Not in our library10.1056/nejm199602013340503

  194. 194.

    Andò S., Barone I., Giordano C., Bonofiglio D., Catalano S. The Multifaceted Mechanism of Leptin Signaling within Tumor Microenvironment in Driving Breast Cancer Growth and Progression. Front. Oncol. 2014;4:340.

    Not in our library10.3389/fonc.2014.00340

  195. 195.

    Akeel Al-hussaniy H., Hikmate Alburghaif A., Akeel Naji M. Leptin hormone and its effectiveness in reproduction, metabolism, immunity, diabetes, hopes and ambitions. J. Med. Life. 2021;14:600-605.

    Not in our library10.25122/jml-2021-0153

  196. 196.

    Lin T.-C., Hsiao M. Leptin and Cancer: Updated Functional Roles in Carcinogenesis, Therapeutic Niches, and Developments. Int. J. Mol. Sci. 2021;22:2870.

    Not in our library10.3390/ijms22062870

  197. 197.

    Barone I., Catalano S., Gelsomino L., Marsico S., Giordano C., Panza S., Bonofiglio D., Bossi G., Covington K.R., Fuqua S.A.W., et al. Leptin Mediates Tumor–Stromal Interactions That Promote the Invasive Growth of Breast Cancer Cells. Cancer Res. 2012;72:1416-1427.

    Not in our library10.1158/0008-5472.can-11-2558

  198. 198.

    Fuentes-Mattei E., Velazquez-Torres G., Phan L., Zhang F., Chou P.-C., Shin J.-H., Choi H.H., Chen J.-S., Zhao R., Chen J., et al. Effects of Obesity on Transcriptomic Changes and Cancer Hallmarks in Estrogen Receptor–Positive Breast Cancer. J. Natl. Cancer Inst. 2014;106:dju158.

    Not in our library10.1093/jnci/dju158

  199. 199.

    Kumar R., Mal K., Razaq M.K., Magsi M., Memon M.K., Memon S., Afroz M.N., Siddiqui H.F., Rizwan A. Association of Leptin With Obesity and Insulin Resistance. Cureus. 2020;12:e12178.

    Not in our library10.7759/cureus.12178

  200. 200.

    Angelucci A., Clementi L., Alesse E., Birbrair A. Leptin in Tumor Microenvironment. Tumor Microenvironment. 2020;Volume 1259:89-112.

    Not in our library10.1007/978-3-030-43093-1_6

  201. 201.

    Pan H., Deng L.-L., Cui J.-Q., Shi L., Yang Y.-C., Luo J.-H., Qin D., Wang L. Association between serum leptin levels and breast cancer risk: An updated systematic review and meta-analysis. Medicine. 2018;97:e11345.

    Not in our library10.1097/md.0000000000011345

  202. 202.

    Hao J.-Q., Zhang Q.-K., Zhou Y.-X., Chen L.-H., Wu P.-F. Association between circulating leptin concentration and G-2548A gene polymorphism in patients with breast cancer: A meta-analysis. Arch. Med. Sci. 2019;15:275-283.

    Not in our library10.5114/aoms.2018.75638

  203. 203.

    Li S.-J., Wei X.-H., Zhan X.-M., He J.-Y., Zeng Y.-Q., Tian X.-M., Yuan S.-T., Sun L. Adipocyte-Derived Leptin Promotes PAI-1-Mediated Breast Cancer Metastasis in a STAT3/MiR-34a Dependent Manner. Cancers. 2020;12:3864.

    Not in our library10.3390/cancers12123864

  204. 204.

    Duan L., Lu Y., Xie W., Nong L., Jia Y., Tan A., Liu Y. Leptin promotes bone metastasis of breast cancer by activating the SDF-1/CXCR4 axis. Aging. 2020;12:16172-16182.

    Not in our library10.18632/aging.103599

  205. 205.
    Obesity and Breast Cancer: Role of Leptin · 2019
    No notice
  206. 206.

    Lipsey C.C., Harbuzariu A., Daley-Brown D., Gonzalez-Perez R.R. Oncogenic role of leptin and Notch interleukin-1 leptin crosstalk outcome in cancer. World J. Methodol. 2016;6:43.

    Not in our library10.5662/wjm.v6.i1.43

  207. 207.
    Leptin-Induced JAK/STAT Signaling and Cancer Growth · 2016
    No notice
  208. 208.

    Maharjan C.K., Mo J., Wang L., Kim M.-C., Wang S., Borcherding N., Vikas P., Zhang W. Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer. Cancers. 2021;14:206.

    Not in our library10.3390/cancers14010206

  209. 209.

    Gelsomino L., Naimo G.D., Malivindi R., Augimeri G., Panza S., Giordano C., Barone I., Bonofiglio D., Mauro L., Catalano S., et al. Knockdown of Leptin Receptor Affects Macrophage Phenotype in the Tumor Microenvironment Inhibiting Breast Cancer Growth and Progression. Cancers. 2020;12:2078.

    Not in our library10.3390/cancers12082078

  210. 210.

    Olea-Flores M., Zuñiga-Eulogio M., Tacuba-Saavedra A., Bueno-Salgado M., Sánchez-Carvajal A., Vargas-Santiago Y., Mendoza-Catalán M.A., Pérez Salazar E., García-Hernández A., Padilla-Benavides T., et al. Leptin Promotes Expression of EMT-Related Transcription Factors and Invasion in a Src and FAK-Dependent Pathway in MCF10A Mammary Epithelial Cells. Cells. 2019;8:1133.

    Not in our library10.3390/cells8101133

  211. 211.

    Linares R.L., Benítez J.G.S., Reynoso M.O., Romero C.G., Sandoval-Cabrera A. Modulation of the leptin receptors expression in breast cancer cell lines exposed to leptin and tamoxifen. Sci. Rep. 2019;9:19189.

    Not in our library10.1038/s41598-019-55674-x

  212. 212.
    The Leptin Receptor Complex: Heavier Than Expected? · 2017
    No notice
  213. 213.

    Cui H., Cai F., Belsham D.D., Cui H., Cai F., Belsham D.D. Leptin signaling in neurotensin neurons involves STAT, MAP kinases ERK1/2, and p38 through c-Fos and ATF1. FASEB J. 2006;20:2654-2656.

    Not in our library10.1096/fj.06-5989fje

  214. 214.

    Cirillo D., Rachiglio A.M., la Montagna R., Giordano A., Normanno N. Leptin signaling in breast cancer: An overview. J. Cell. Biochem. 2008;105:956-964.

    Not in our library10.1002/jcb.21911

  215. 215.

    Gualillo O., Eiras S., White D.W., Diéguez C., Casanueva F.F. Leptin promotes the tyrosine phosphorylation of SHC proteins and SHC association with GRB2. Mol. Cell. Endocrinol. 2002;190:83-89.

    Not in our library10.1016/s0303-7207(02)00012-6

  216. 216.

    Delort L., Rossary A., Farges M.-C., Vasson M.-P., Caldefie-Chézet F. Leptin, adipocytes and breast cancer: Focus on inflammation and anti-tumor immunity. Life Sci. 2015;140:37-48.

    Not in our library10.1016/j.lfs.2015.04.012

  217. 217.

    Mahbouli S., Der Vartanian A., Ortega S., Rougé S., Vasson M.-P., Rossary A. Leptin induces ROS via NOX5 in healthy and neoplastic mammary epithelial cells. Oncol. Rep. 2017;38:3254-3264.

    Not in our library10.3892/or.2017.6009

  218. 218.

    del Mar Blanquer-Rosselló M., Oliver J., Sastre-Serra J., Valle A., Roca P. Leptin regulates energy metabolism in MCF-7 breast cancer cells. Int. J. Biochem. Cell Biol. 2016;72:18-26.

    Not in our library10.1016/j.biocel.2016.01.002

  219. 219.

    Park J., Scherer P.E. Leptin and cancer: From cancer stem cells to metastasis. Endocr. Relat. Cancer. 2011;18:C25-C29.

    Not in our library10.1530/erc-11-0163

  220. 220.

    Newman G., Gonzalez-Perez R.R. Leptin–cytokine crosstalk in breast cancer. Mol. Cell. Endocrinol. 2014;382:570-582.

    Not in our library10.1016/j.mce.2013.03.025

  221. 221.

    Giordano C., Chemi F., Panza S., Barone I., Bonofiglio D., Lanzino M., Cordella A., Campana A., Hashim A., Rizza P., et al. Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity. Oncotarget. 2016;7:1262-1275.

    Not in our library10.18632/oncotarget.6014

  222. 222.

    Shpilman M., Niv-Spector L., Katz M., Varol C., Solomon G., Ayalon-Soffer M., Boder E., Halpern Z., Elinav E., Gertler A. Development and Characterization of High Affinity Leptins and Leptin Antagonists. J. Biol. Chem. 2011;286:4429-4442.

    Not in our library10.1074/jbc.m110.196402

  223. 223.

    Avtanski D.B., Nagalingam A., Bonner M.Y., Arbiser J.L., Saxena N.K., Sharma D. Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer. Oncotarget. 2015;6:29947-29962.

    Not in our library10.18632/oncotarget.4937

  224. 224.
    TNF-α/NF-κB/Snail pathway in cancer cell migration and invasion · 2010
    No notice
  225. 225.

    Cawthorn W.P., Sethi J.K. TNF-α and adipocyte biology. FEBS Lett. 2008;582:117-131.

    Not in our library10.1016/j.febslet.2007.11.051

  226. 226.

    Sethi J.K., Hotamisligil G.S. Metabolic Messengers: Tumour necrosis factor. Nat. Metab. 2021;3:1302-1312.

    Not in our library10.1038/s42255-021-00470-z

  227. 227.

    Storci G., Sansone P., Mari S., D’Uva G., Tavolari S., Guarnieri T., Taffurelli M., Ceccarelli C., Santini D., Chieco P., et al. TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype. J. Cell. Physiol. 2010;225:682-691.

    Not in our library10.1002/jcp.22264

  228. 228.

    Mantovani A., Marchesi F., Porta C., Sica A., Allavena P. Inflammation and cancer: Breast cancer as a prototype. Breast. 2007;16:27-33.

    Not in our library10.1016/j.breast.2007.07.013

  229. 229.

    Cohen E.N., Gao H., Anfossi S., Mego M., Reddy N.G., Debeb B., Giordano A., Tin S., Wu Q., Garza R.J., et al. Inflammation Mediated Metastasis: Immune Induced Epithelial-To-Mesenchymal Transition in Inflammatory Breast Cancer Cells. PLoS ONE. 2015;10:e0132710.

    Not in our library10.1371/journal.pone.0132710

  230. 230.

    Macdiarmid F., Wang D., Duncan L.J., Purohit A., Ghilchik M.W., Reed M.J. Stimulation of aromatase activity in breast fibroblasts by tumor necrosis factor. Mol. Cell. Endocrinol. 1994;106:17-21.

    Not in our library10.1016/0303-7207(94)90181-3

  231. 231.

    Liu W., Lu X., Shi P., Yang G., Zhou Z., Li W., Mao X., Jiang D., Chen C. TNF-α increases breast cancer stem-like cells through up-regulating TAZ expression via the non-canonical NF-κB pathway. Sci. Rep. 2020;10:1804.

    Not in our library10.1038/s41598-020-58642-y

  232. 232.

    Devin A., Lin Y., Yamaoka S., Li Z., Karin M., Liu Z. The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF. Mol. Cell. Biol. 2001;21:3986-3994.

    Not in our library10.1128/mcb.21.12.3986-3994.2001

  233. 233.

    Li C.-W., Xia W., Huo L., Lim S.-O., Wu Y., Hsu J.L., Chao C.-H., Yamaguchi H., Yang N.-K., Ding Q., et al. Epithelial–Mesenchymal Transition Induced by TNF-α Requires NF-κB–Mediated Transcriptional Upregulation of Twist1. Cancer Res. 2012;72:1290-1300.

    Not in our library10.1158/0008-5472.can-11-3123

  234. 234.

    Wolczyk D., Zaremba-Czogalla M., Hryniewicz-Jankowska A., Tabola R., Grabowski K., Sikorski A.F., Augoff K. TNF-α promotes breast cancer cell migration and enhances the concentration of membrane-associated proteases in lipid rafts. Cell. Oncol. 2016;39:353-363.

    Not in our library10.1007/s13402-016-0280-x

  235. 235.

    Robinson S.C., Scott K.A., Balkwill F.R. Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-α. Eur. J. Immunol. 2002;32:404-412.

    Not in our library10.1002/1521-4141(200202)32:2<404::aid-immu404>3.0.co;2-x

  236. 236.

    Raghu H., Sodadasu P.K., Malla R.R., Gondi C.S., Estes N., Rao J.S. Localization of uPAR and MMP-9 in lipid rafts is critical for migration, invasion and angiogenesis in human breast cancer cells. BMC Cancer. 2010;10:647.

    Not in our library10.1186/1471-2407-10-647

  237. 237.

    Lane M.D., Tang Q.-Q., Jiang M.-S. Role of the CCAAT Enhancer Binding Proteins (C/EBPs) in Adipocyte Differentiation. Biochem. Biophys. Res. Commun. 1999;266:677-683.

    Not in our library10.1006/bbrc.1999.1885

  238. 238.

    Martínez-Chacón G., Brown K.A., Docanto M.M., Kumar H., Salminen S., Saarinen N., Mäkelä S. IL-10 suppresses TNF-α-induced expression of human aromatase gene in mammary adipose tissue. FASEB J. 2018;32:3361-3370.

    Not in our library10.1096/fj.201700938rrr

  239. 239.

    Yu H., Aravindan N., Xu J., Natarajan M. Inter- and intra-cellular mechanism of NF-kB-dependent survival advantage and clonal expansion of radio-resistant cancer cells. Cell. Signal. 2017;31:105-111.

    Not in our library10.1016/j.cellsig.2017.01.011

  240. 240.

    Activation of Nuclear Factor-Kappa B Is Linked to Resistance to Neoadjuvant Chemotherapy in Breast Cancer Patients.

    Not in our library

  241. 241.

    Zhang Z., Lin G., Yan Y., Li X., Hu Y., Wang J., Yin B., Wu Y., Li Z., Yang X.-P. Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells. Oncogene. 2018;37:3456-3470.

    Not in our library10.1038/s41388-018-0221-4

  242. 242.

    Torrey H., Butterworth J., Mera T., Okubo Y., Wang L., Baum D., Defusco A., Plager S., Warden S., Huang D., et al. Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs. Sci. Signal. 2017;10:eaaf8608.

    Not in our library10.1126/scisignal.aaf8608

  243. 243.

    Rubio M.F., Werbajh S., Cafferata E.G.A., Quaglino A., Coló G.P., Nojek I.M., Kordon E.C., Nahmod V.E., Costas M.A. TNF-α enhances estrogen-induced cell proliferation of estrogen-dependent breast tumor cells through a complex containing nuclear factor-kappa B. Oncogene. 2006;25:1367-1377.

    Not in our library10.1038/sj.onc.1209176

  244. 244.

    Transactivation of ErbB-2 Induced by Tumor Necrosis Factor Alpha Promotes NF-kappaB Activation and Breast Cancer Cell Proliferation.

    Not in our library10.1007/s10549-009-0546-3

  245. 245.

    Sutton C.E., Lalor S.J., Sweeney C.M., Brereton C.F., Lavelle E.C., Mills K.H.G. Interleukin-1 and IL-23 Induce Innate IL-17 Production from γδ T Cells, Amplifying Th17 Responses and Autoimmunity. Immunity. 2009;31:331-341.

    Not in our library10.1016/j.immuni.2009.08.001

  246. 246.

    Kaler P., Augenlicht L., Klampfer L. Macrophage-derived IL-1β stimulates Wnt signaling and growth of colon cancer cells: A crosstalk interrupted by vitamin D3. Oncogene. 2009;28:3892-3902.

    Not in our library10.1038/onc.2009.247

  247. 247.

    Afonina I.S., Müller C., Martin S.J., Beyaert R. Proteolytic Processing of Interleukin-1 Family Cytokines: Variations on a Common Theme. Immunity. 2015;42:991-1004.

    Not in our library10.1016/j.immuni.2015.06.003

  248. 248.

    Schroder K., Tschopp J. The Inflammasomes. Cell. 2010;140:821-832.

    Not in our library10.1016/j.cell.2010.01.040

  249. 249.

    McMahan C.J., Slack J.L., Mosley B., Cosman D., Lupton S.D., Brunton L.L., Grubin C.E., Wignall J.M., Jenkins N.A., Brannan C.I. A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. EMBO J. 1991;10:2821-2832.

    Not in our library10.1002/j.1460-2075.1991.tb07831.x

  250. 250.

    Oh K., Lee O.-Y., Park Y., Seo M.W., Lee D.-S. IL-1β induces IL-6 production and increases invasiveness and estrogen-independent growth in a TG2-dependent manner in human breast cancer cells. BMC Cancer. 2016;16:724.

    Not in our library10.1186/s12885-016-2746-7

  251. 251.

    Nutter F., Holen I., Brown H.K., Cross S.S., Evans C.A., Walker M., Coleman R.E., Westbrook J.A., Selby P.J., Brown J.E., et al. Different molecular profiles are associated with breast cancer cell homing compared with colonisation of bone: Evidence using a novel bone-seeking cell line. Endocr. Relat. Cancer. 2014;21:327-341.

    Not in our library10.1530/erc-13-0158

  252. 252.

    Ben-Sasson S.Z., Hogg A., Hu-Li J., Wingfield P., Chen X., Crank M., Caucheteux S., Ratner-Hurevich M., Berzofsky J.A., Nir-Paz R., et al. IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells. J. Exp. Med. 2013;210:491-502.

    Not in our library10.1084/jem.20122006

  253. 253.

    Mon N.N., Senga T., Ito S. Interleukin-1β activates focal adhesion kinase and Src to induce matrix metalloproteinase-9 production and invasion of MCF-7 breast cancer cells. Oncol. Lett. 2017;13:955-960.

    Not in our library10.3892/ol.2016.5521

  254. 254.

    Espinoza-Sánchez N.A., Chimal-Ramírez G.K., Mantilla A., Fuentes-Pananá E.M. IL-1β, IL-8, and Matrix Metalloproteinases-1, -2, and -10 Are Enriched upon Monocyte–Breast Cancer Cell Cocultivation in a Matrigel-Based Three-Dimensional System. Front. Immunol. 2017;8:205.

    Not in our library10.3389/fimmu.2017.00205

  255. 255.

    Escobar P., Bouclier C., Serret J., Bièche I., Brigitte M., Caicedo A., Sanchez E., Vacher S., Vignais M.-L., Bourin P., et al. IL-1β produced by aggressive breast cancer cells is one of the factors that dictate their interactions with mesenchymal stem cells through chemokine production. Oncotarget. 2015;6:29034-29047.

    Not in our library10.18632/oncotarget.4732

  256. 256.

    Chen Q., Wang J., Zhang Q., Zhang J., Lou Y., Yang J., Chen Y., Wei T., Zhang J., Fu Q., et al. Tumour cell-derived debris and IgG synergistically promote metastasis of pancreatic cancer by inducing inflammation via tumour-associated macrophages. Br. J. Cancer. 2019;121:786-795.

    Not in our library10.1038/s41416-019-0595-2

  257. 257.

    Jang J.-H., Kim D.-H., Lim J.M., Lee J.W., Jeong S.J., Kim K.P., Surh Y.-J. Breast Cancer Cell–Derived Soluble CD44 Promotes Tumor Progression by Triggering Macrophage IL1β Production. Cancer Res. 2020;80:1342-1356.

    Not in our library10.1158/0008-5472.can-19-2288

  258. 258.

    Shchors K., Shchors E., Rostker F., Lawlor E.R., Brown-Swigart L., Evan G.I. The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1β. Genes Dev. 2006;20:2527-2538.

    Not in our library10.1101/gad.1455706

  259. 259.

    Kolb R., Kluz P., Tan Z.W., Borcherding N., Bormann N., Vishwakarma A., Balcziak L., Zhu P., Davies B.S.J., Gourronc F., et al. Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4. Oncogene. 2019;38:2351-2363.

    Not in our library10.1038/s41388-018-0592-6

  260. 260.

    Zhang L., Zhou Y., Sun X., Zhou J., Yang P. CXCL12 overexpression promotes the angiogenesis potential of periodontal ligament stem cells. Sci. Rep. 2017;7:10286.

    Not in our library10.1038/s41598-017-10971-1

  261. 261.

    Kaplanov I., Carmi Y., Kornetsky R., Shemesh A., Shurin G.V., Shurin M.R., Dinarello C.A., Voronov E., Apte R.N. Blocking IL-1β reverses the immunosuppression in mouse breast cancer and synergizes with anti–PD-1 for tumor abrogation. Proc. Natl. Acad. Sci. USA. 2019;116:1361-1369.

    Not in our library10.1073/pnas.1812266115

  262. 262.
    The role of IL-1B in breast cancer bone metastasis · 2018
    No notice
  263. 263.

    Muraguchi A., Hirano T., Tang B., Matsuda T., Horii Y., Nakajima K., Kishimoto T. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J. Exp. Med. 1988;167:332-344.

    Not in our library10.1084/jem.167.2.332

  264. 264.

    Murakami M., Kamimura D., Hirano T. Pleiotropy and Specificity: Insights from the Interleukin 6 Family of Cytokines. Immunity. 2019;50:812-831.

    Not in our library10.1016/j.immuni.2019.03.027

  265. 265.

    Yoon S., Woo S.U., Kang J.H., Kim K., Kwon M.-H., Park S., Shin H.-J., Gwak H.-S., Chwae Y.-J. STAT3 transcriptional factor activated by reactive oxygen species induces IL6 in starvation-induced autophagy of cancer cells. Autophagy. 2010;6:1125-1138.

    Not in our library10.4161/auto.6.8.13547

  266. 266.

    Diehl S., Rincón M. The two faces of IL-6 on Th1/Th2 differentiation. Mol. Immunol. 2002;39:531-536.

    Not in our library10.1016/s0161-5890(02)00210-9

  267. 267.

    Kimura A., Kishimoto T. IL-6: Regulator of Treg/Th17 balance. Eur. J. Immunol. 2010;40:1830-1835.

    Not in our library10.1002/eji.201040391

  268. 268.

    Rose-John S. IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6. Int. J. Biol. Sci. 2012;8:1237-1247.

    Not in our library10.7150/ijbs.4989

  269. 269.

    Angell H., Galon J. From the immune contexture to the Immunoscore: The role of prognostic and predictive immune markers in cancer. Curr. Opin. Immunol. 2013;25:261-267.

    Not in our library10.1016/j.coi.2013.03.004

  270. 270.

    Santer F.R., Malinowska K., Culig Z., Cavarretta I.T. Interleukin-6 trans-signalling differentially regulates proliferation, migration, adhesion and maspin expression in human prostate cancer cells. Endocr. Relat. Cancer. 2010;17:241-253.

    Not in our library10.1677/erc-09-0200

  271. 271.

    Naugler W.E., Karin M. The wolf in sheep’s clothing: The role of interleukin-6 in immunity, inflammation and cancer. Trends Mol. Med. 2008;14:109-119.

    Not in our library10.1016/j.molmed.2007.12.007

  272. 272.

    Grivennikov S.I., Greten F.R., Karin M. Immunity, Inflammation, and Cancer. Cell. 2010;140:883-899.

    Not in our library10.1016/j.cell.2010.01.025

  273. 273.

    Liu S., Ginestier C., Ou S.J., Clouthier S.G., Patel S.H., Monville F., Korkaya H., Heath A., Dutcher J., Kleer C.G., et al. Breast Cancer Stem Cells Are Regulated by Mesenchymal Stem Cells through Cytokine Networks. Cancer Res. 2011;71:614-624.

    Not in our library10.1158/0008-5472.can-10-0538

  274. 274.

    Dethlefsen C., Højfeldt G., Hojman P. The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res. Treat. 2013;138:657-664.

    Not in our library10.1007/s10549-013-2488-z

  275. 275.

    Oh K., Ko E., Kim H.S., Park A.K., Moon H.-G., Noh D.-Y., Lee D.-S. Transglutaminase 2 facilitates the distant hematogenous metastasis of breast cancer by modulating interleukin-6 in cancer cells. Breast Cancer Res. 2011;13:R96.

    Not in our library10.1186/bcr3034

  276. 276.

    Purohit A., Reed M.J. Regulation of estrogen synthesis in postmenopausal women. Steroids. 2002;67:979-983.

    Not in our library10.1016/s0039-128x(02)00046-6

  277. 277.

    Erez N., Glanz S., Raz Y., Avivi C., Barshack I. Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors. Biochem. Biophys. Res. Commun. 2013;437:397-402.

    Not in our library10.1016/j.bbrc.2013.06.089

  278. 278.

    Sansone P., Storci G., Tavolari S., Guarnieri T., Giovannini C., Taffurelli M., Ceccarelli C., Santini D., Paterini P., Marcu K.B., et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J. Clin. Investig. 2007;117:3988-4002.

    Not in our library10.1172/jci32533

  279. 279.

    Bromberg J.F., Wrzeszczynska M.H., Devgan G., Zhao Y., Pestell R.G., Albanese C., Darnell J.E. Stat3 as an Oncogene. Cell. 1999;98:295-303.

    Not in our library10.1016/s0092-8674(00)81959-5

  280. 280.

    Gritsko T., Williams A., Turkson J., Kaneko S., Bowman T., Huang M., Nam S., Eweis I., Diaz N., Sullivan D., et al. Persistent Activation of Stat3 Signaling Induces Survivin Gene Expression and Confers Resistance to Apoptosis in Human Breast Cancer Cells. Clin. Cancer Res. 2006;12:11-19.

    Not in our library10.1158/1078-0432.ccr-04-1752

  281. 281.

    Kiuchi N., Nakajima K., Ichiba M., Fukada T., Narimatsu M., Mizuno K., Hibi M., Hirano T. STAT3 Is Required for the gp130-mediated Full Activation of the c-myc Gene. J. Exp. Med. 1999;189:63-73.

    Not in our library10.1084/jem.189.1.63

  282. 282.

    Thiem S., Pierce T.P., Palmieri M., Putoczki T.L., Buchert M., Preaudet A., Farid R.O., Love C., Catimel B., Lei Z., et al. mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice. J. Clin. Investig. 2013;123:767-781.

    Not in our library10.1172/jci65086

  283. 283.

    Rebouissou S., Amessou M., Couchy G., Poussin K., Imbeaud S., Pilati C., Izard T., Balabaud C., Bioulac-Sage P., Zucman-Rossi J. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature. 2009;457:200-204.

    Not in our library10.1038/nature07475

  284. 284.

    Pilati C., Amessou M., Bihl M.P., Balabaud C., Van Nhieu J.T., Paradis V., Nault J.C., Izard T., Bioulac-Sage P., Couchy G., et al. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J. Exp. Med. 2011;208:1359-1366.

    Not in our library10.1084/jem.20110283

  285. 285.

    Shirogane T., Fukada T., Muller J.M.M., Shima D.T., Hibi M., Hirano T. Synergistic Roles for Pim-1 and c-Myc in STAT3-Mediated Cell Cycle Progression and Antiapoptosis. Immunity. 1999;11:709-719.

    Not in our library10.1016/s1074-7613(00)80145-4

  286. 286.

    Benoy I., Salgado R., Colpaert C., Weytjens R., Vermeulen P.B., Dirix L.Y. Serum Interleukin 6, Plasma VEGF, Serum VEGF, and VEGF Platelet Load in Breast Cancer Patients. Clin. Breast Cancer. 2002;2:311-315.

    Not in our library10.3816/cbc.2002.n.008

  287. 287.

    Garcia-Tunon I., Ricote M., Ruiz A., Fraile B., Paniagua R., Royuela M. IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma. Histopathology. 2005;47:82-89.

    Not in our library10.1111/j.1365-2559.2005.02178.x

  288. 288.

    Hirano T. IL-6 in inflammation, autoimmunity and cancer. Int. Immunol. 2021;33:127-148.

    Not in our library10.1093/intimm/dxaa078

  289. 289.

    Sansone P., Bromberg J. Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies. J. Clin. Oncol. 2012;30:1005-1014.

    Not in our library10.1200/jco.2010.31.8907

  290. 290.

    Shibayama O., Yoshiuchi K., Inagaki M., Matsuoka Y., Yoshikawa E., Sugawara Y., Akechi T., Wada N., Imoto S., Murakami K., et al. Association between adjuvant regional radiotherapy and cognitive function in breast cancer patients treated with conservation therapy. Cancer Med. 2014;3:702-709.

    Not in our library10.1002/cam4.174

  291. 291.

    Morrow R.J., Allam A.H., Yeo B., Deb S., Murone C., Lim E., Johnstone C.N., Ernst M. Paracrine IL-6 Signaling Confers Proliferation between Heterogeneous Inflammatory Breast Cancer Sub-Clones. Cancers. 2022;14:2292.

    Not in our library10.3390/cancers14092292

  292. 292.

    Li H., Xiao H., Lin L., Jou D., Kumari V., Lin J., Li C. Drug Design Targeting Protein–Protein Interactions (PPIs) Using Multiple Ligand Simultaneous Docking (MLSD) and Drug Repositioning: Discovery of Raloxifene and Bazedoxifene as Novel Inhibitors of IL-6/GP130 Interface. J. Med. Chem. 2014;57:632-641.

    Not in our library10.1021/jm401144z

  293. 293.

    Chen J., Wei Y., Yang W., Huang Q., Chen Y., Zeng K., Chen J. IL-6: The Link Between Inflammation, Immunity and Breast Cancer. Front. Oncol. 2022;12:903800.

    Not in our library10.3389/fonc.2022.903800

  294. 294.

    Modi W.S., Dean M., Seuanez H.N., Mukaida N., Matsushima K., O’Brien S.J. Monocyte-derived neutrophil chemotactic factor (MDNCF/IL-8) resides in a gene cluster along with several other members of the platelet factor 4 gene superfamily. Hum. Genet. 1990;84:185-187.

    Not in our library10.1007/bf00208938

  295. 295.

    Harada A., Sekido N., Akahoshi T., Wada T., Mukaida N., Matsushima K. Essential involvement of interleukin-8 (IL-8) in acute inflammation. J. Leukoc. Biol. 1994;56:559-564.

    Not in our library10.1002/jlb.56.5.559

  296. 296.

    Baggiolini M., Dahinden C.A. CC chemokines in allergic inflammation. Immunol. Today. 1994;15:127-133.

    Not in our library10.1016/0167-5699(94)90156-2

  297. 297.

    Azar Sharabiani M.T., Vermeulen R., Scoccianti C., Hosnijeh F.S., Minelli L., Sacerdote C., Palli D., Krogh V., Tumino R., Chiodini P., et al. Immunologic profile of excessive body weight. Biomarkers. 2011;16:243-251.

    Not in our library10.3109/1354750x.2010.547948

  298. 298.

    Alfaro C., Sanmamed M.F., Rodríguez-Ruiz M.E., Teijeira Á., Oñate C., González Á., Ponz M., Schalper K.A., Pérez-Gracia J.L., Melero I. Interleukin-8 in cancer pathogenesis, treatment and follow-up. Cancer Treat. Rev. 2017;60:24-31.

    Not in our library10.1016/j.ctrv.2017.08.004

  299. 299.

    Todorović-Raković N., Milovanović J. Interleukin-8 in Breast Cancer Progression. J. Interferon Cytokine Res. 2013;33:563-570.

    Not in our library10.1089/jir.2013.0023

  300. 300.

    Korkaya H., Kim G., Davis A., Malik F., Henry N.L., Ithimakin S., Quraishi A.A., Tawakkol N., D’Angelo R., Paulson A.K., et al. Activation of an IL6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2+ Breast Cancer by Expanding the Cancer Stem Cell Population. Mol. Cell. 2012;47:570-584.

    Not in our library10.1016/j.molcel.2012.06.014

  301. 301.

    Bohrer L.R., Schwertfeger K.L. Macrophages Promote Fibroblast Growth Factor Receptor-Driven Tumor Cell Migration and Invasion in a Cxcr2-Dependent Manner. Mol. Cancer Res. 2012;10:1294-1305.

    Not in our library10.1158/1541-7786.mcr-12-0275

  302. 302.

    Joseph P.R.B., Rajarathnam K. Solution NMR characterization of WTCXCL8 monomer and dimer binding to CXCR1 N-terminal domain: Differential Activities of CXCL8 Monomer and Dimer. Protein Sci. 2015;24:81-92.

    Not in our library10.1002/pro.2590

  303. 303.

    Schumacher C., Clark-Lewis I., Baggiolini M., Moser B. High- and low-affinity binding of GRO alpha and neutrophil-activating peptide 2 to interleukin 8 receptors on human neutrophils. Proc. Natl. Acad. Sci. USA. 1992;89:10542-10546.

    Not in our library10.1073/pnas.89.21.10542

  304. 304.

    Brat D.J., Bellail A.C., Van Meir E.G. The role of interleukin-8 and its receptors in gliomagenesis and tumoralangiogenesis. Neuro-Oncol. 2005;7:122-133.

    Not in our library10.1215/s1152851704001061

  305. 305.

    Li A., Dubey S., Varney M.L., Dave B.J., Singh R.K. IL-8 Directly Enhanced Endothelial Cell Survival, Proliferation, and Matrix Metalloproteinases Production and Regulated Angiogenesis. J. Immunol. 2003;170:3369-3376.

    Not in our library10.4049/jimmunol.170.6.3369

  306. 306.

    Lang K., Niggemann B., Zanker K.S., Entschladen F. Signal processing in migrating T24 human bladder carcinoma cells: Role of the autocrine interleukin-8 loop. Int. J. Cancer. 2002;99:673-680.

    Not in our library10.1002/ijc.10424

  307. 307.

    Richardson R.M., Ali H., Pridgen B.C., Haribabu B., Snyderman R. Multiple Signaling Pathways of Human Interleukin-8 Receptor A. J. Biol. Chem. 1998;273:10690-10695.

    Not in our library10.1074/jbc.273.17.10690

  308. 308.
    Increased expression of MMP-9 and IL-8 are correlated with poor prognosis of Bladder Cancer · 2012
    No notice
  309. 309.

    Deng F., Weng Y., Li X., Wang T., Fan M., Shi Q. Overexpression of IL-8 promotes cell migration via PI3K-Akt signaling pathway and EMT in triple-negative breast cancer. Pathol.-Res. Pract. 2021;223:152824.

    Not in our library10.1016/j.prp.2020.152824

  310. 310.

    Huang W., Chen Z., Zhang L., Tian D., Wang D., Fan D., Wu K., Xia L. Interleukin-8 Induces Expression of FOXC1 to Promote Transactivation of CXCR1 and CCL2 in Hepatocellular Carcinoma Cell Lines and Formation of Metastases in Mice. Gastroenterology. 2015;149:1053-1067.e14.

    Not in our library10.1053/j.gastro.2015.05.058

  311. 311.

    Paulitti A., Andreuzzi E., Bizzotto D., Pellicani R., Tarticchio G., Marastoni S., Pastrello C., Jurisica I., Ligresti G., Bucciotti F., et al. The ablation of the matricellular protein EMILIN2 causes defective vascularization due to impaired EGFR-dependent IL-8 production affecting tumor growth. Oncogene. 2018;37:3399-3414.

    Not in our library10.1038/s41388-017-0107-x

  312. 312.

    Schraufstatter I.U., Trieu K., Zhao M., Rose D.M., Terkeltaub R.A., Burger M. IL-8-Mediated Cell Migration in Endothelial Cells Depends on Cathepsin B Activity and Transactivation of the Epidermal Growth Factor Receptor. J. Immunol. 2003;171:6714-6722.

    Not in our library10.4049/jimmunol.171.12.6714

  313. 313.

    Petreaca M.L., Yao M., Liu Y., DeFea K., Martins-Green M. Transactivation of Vascular Endothelial Growth Factor Receptor-2 by Interleukin-8 (IL-8/CXCL8) Is Required for IL-8/CXCL8-induced Endothelial Permeability. Mol. Biol. Cell. 2007;18:5014-5023.

    Not in our library10.1091/mbc.e07-01-0004

  314. 314.

    Fousek K., Horn L.A., Palena C. Interleukin-8: A chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression. Pharmacol. Ther. 2021;219:107692.

    Not in our library10.1016/j.pharmthera.2020.107692

  315. 315.

    Rubinstein-Achiasaf L., Morein D., Ben-Yaakov H., Liubomirski Y., Meshel T., Elbaz E., Dorot O., Pichinuk E., Gershovits M., Weil M., et al. Persistent Inflammatory Stimulation Drives the Conversion of MSCs to Inflammatory CAFs That Promote Pro-Metastatic Characteristics in Breast Cancer Cells. Cancers. 2021;13:1472.

    Not in our library10.3390/cancers13061472

  316. 316.

    Benoy I.H., Salgado R., Van Dam P., Geboers K., Van Marck E., Scharpé S., Vermeulen P.B., Dirix L.Y. Increased Serum Interleukin-8 in Patients with Early and Metastatic Breast Cancer Correlates with Early Dissemination and Survival. Clin. Cancer Res. 2004;10:7157-7162.

    Not in our library10.1158/1078-0432.ccr-04-0812

  317. 317.

    Chin A.R., Wang S.E. Cytokines driving breast cancer stemness. Mol. Cell. Endocrinol. 2014;382:598-602.

    Not in our library10.1016/j.mce.2013.03.024

  318. 318.

    Liu Q., Li A., Tian Y., Wu J.D., Liu Y., Li T., Chen Y., Han X., Wu K. The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev. 2016;31:61-71.

    Not in our library10.1016/j.cytogfr.2016.08.002

  319. 319.

    Han Z.-J., Li Y.-B., Yang L.-X., Cheng H.-J., Liu X., Chen H. Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy. Molecules. 2021;27:137.

    Not in our library10.3390/molecules27010137

  320. 320.

    White J.R., Lee J.M., Young P.R., Hertzberg R.P., Jurewicz A.J., Chaikin M.A., Widdowson K., Foley J.J., Martin L.D., Griswold D.E., et al. Identification of a Potent, Selective Non-peptide CXCR2 Antagonist That Inhibits Interleukin-8-induced Neutrophil Migration. J. Biol. Chem. 1998;273:10095-10098.

    Not in our library10.1074/jbc.273.17.10095

  321. 321.

    Kim S., You D., Jeong Y., Yoon S.Y., Kim S.A., Kim S.W., Nam S.J., Lee J.E. WNT5A augments cell invasiveness by inducing CXCL8 in HER2-positive breast cancer cells. Cytokine. 2020;135:155213.

    Not in our library10.1016/j.cyto.2020.155213

  322. 322.

    Singh J.K., Farnie G., Bundred N.J., Simões B.M., Shergill A., Landberg G., Howell S.J., Clarke R.B. Targeting CXCR1/2 Significantly Reduces Breast Cancer Stem Cell Activity and Increases the Efficacy of Inhibiting HER2 via HER2-Dependent and -Independent Mechanisms. Clin. Cancer Res. 2013;19:643-656.

    Not in our library10.1158/1078-0432.ccr-12-1063

  323. 323.

    Ginestier C., Liu S., Diebel M.E., Korkaya H., Luo M., Brown M., Wicinski J., Cabaud O., Charafe-Jauffret E., Birnbaum D., et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J. Clin. Investig. 2010;120:485-497.

    Not in our library10.1172/jci39397

  324. 324.

    Moseley T.A., Haudenschild D.R., Rose L., Reddi A.H. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003;14:155-174.

    Not in our library10.1016/s1359-6101(03)00002-9

  325. 325.

    Korn T., Bettelli E., Oukka M., Kuchroo V.K. IL-17 and Th17 Cells. Annu. Rev. Immunol. 2009;27:485-517.

    Not in our library10.1146/annurev.immunol.021908.132710

  326. 326.

    Onishi R.M., Gaffen S.L. Interleukin-17 and its target genes: Mechanisms of interleukin-17 function in disease. Immunology. 2010;129:311-321.

    Not in our library10.1111/j.1365-2567.2009.03240.x

  327. 327.

    Aggarwal S., Ghilardi N., Xie M.-H., de Sauvage F.J., Gurney A.L. Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17. J. Biol. Chem. 2003;278:1910-1914.

    Not in our library10.1074/jbc.m207577200

  328. 328.

    McGeachy M.J., Cua D.J., Gaffen S.L. The IL-17 Family of Cytokines in Health and Disease. Immunity. 2019;50:892-906.

    Not in our library10.1016/j.immuni.2019.03.021

  329. 329.

    Mangan P.R., Harrington L.E., O’Quinn D.B., Helms W.S., Bullard D.C., Elson C.O., Hatton R.D., Wahl S.M., Schoeb T.R., Weaver C.T. Transforming growth factor-β induces development of the TH17 lineage. Nature. 2006;441:231-234.

    Not in our library10.1038/nature04754

  330. 330.

    Ivanov I.I., McKenzie B.S., Zhou L., Tadokoro C.E., Lepelley A., Lafaille J.J., Cua D.J., Littman D.R. The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells. Cell. 2006;126:1121-1133.

    Not in our library10.1016/j.cell.2006.07.035

  331. 331.

    Mimpen J.Y., Snelling S.J.B., Carr A.J., Dakin S.G. Interleukin-17 Cytokines and Receptors: Potential Amplifiers of Tendon Inflammation. Front. Bioeng. Biotechnol. 2021;9:795830.

    Not in our library10.3389/fbioe.2021.795830

  332. 332.

    Huang Q., Duan L., Qian X., Fan J., Lv Z., Zhang X., Han J., Wu F., Guo M., Hu G., et al. IL-17 Promotes Angiogenic Factors IL-6, IL-8, and Vegf Production via Stat1 in Lung Adenocarcinoma. Sci. Rep. 2016;6:36551.

    Not in our library10.1038/srep36551

  333. 333.

    Kennedy J., Rossi D.L., Zurawski S.M., Vega F., Kastelein R.A., Wagner J.L., Hannum C.H., Zlotnik A. Mouse IL-17: A Cytokine Preferentially Expressed by αβTCR+CD4—CD8—T Cells. J. Interferon Cytokine Res. 1996;16:611-617.

    Not in our library10.1089/jir.1996.16.611

  334. 334.

    Shalom-Barak T., Quach J., Lotz M. Interleukin-17-induced Gene Expression in Articular Chondrocytes Is Associated with Activation of Mitogen-activated Protein Kinases and NF-κB. J. Biol. Chem. 1998;273:27467-27473.

    Not in our library10.1074/jbc.273.42.27467

  335. 335.

    Chen X., Chang L., Li X., Huang J., Yang L., Lai X., Huang Z., Wang Z., Wu X., Zhao J., et al. Tc17/IL-17A Up-Regulated the Expression of MMP-9 via NF-κB Pathway in Nasal Epithelial Cells of Patients With Chronic Rhinosinusitis. Front. Immunol. 2018;9:2121.

    Not in our library10.3389/fimmu.2018.02121

  336. 336.

    Numasaki M., Watanabe M., Suzuki T., Takahashi H., Nakamura A., McAllister F., Hishinuma T., Goto J., Lotze M.T., Kolls J.K., et al. IL-17 Enhances the Net Angiogenic Activity and In Vivo Growth of Human Non-Small Cell Lung Cancer in SCID Mice through Promoting CXCR-2-Dependent Angiogenesis. J. Immunol. 2005;175:6177-6189.

    Not in our library10.4049/jimmunol.175.9.6177

  337. 337.

    Su X., Ye J., Hsueh E.C., Zhang Y., Hoft D.F., Peng G. Tumor Microenvironments Direct the Recruitment and Expansion of Human Th17 Cells. J. Immunol. 2010;184:1630-1641.

    Not in our library10.4049/jimmunol.0902813

  338. 338.

    Alinejad V., Dolati S., Motallebnezhad M., Yousefi M. The role of IL17B-IL17RB signaling pathway in breast cancer. Biomed. Pharmacother. 2017;88:795-803.

    Not in our library10.1016/j.biopha.2017.01.120

  339. 339.

    Cochaud S., Giustiniani J., Thomas C., Laprevotte E., Garbar C., Savoye A.-M., Curé H., Mascaux C., Alberici G., Bonnefoy N., et al. IL-17A is produced by breast cancer TILs and promotes chemoresistance and proliferation through ERK1/2. Sci. Rep. 2013;3:3456.

    Not in our library10.1038/srep03456

  340. 340.

    Suryawanshi A., Veiga-Parga T., Reddy P.B.J., Rajasagi N.K., Rouse B.T. IL-17A Differentially Regulates Corneal Vascular Endothelial Growth Factor (VEGF)-A and Soluble VEGF Receptor 1 Expression and Promotes Corneal Angiogenesis after Herpes Simplex Virus Infection. J. Immunol. 2012;188:3434-3446.

    Not in our library10.4049/jimmunol.1102602

  341. 341.

    Muromoto R., Hirao T., Tawa K., Hirashima K., Kon S., Kitai Y., Matsuda T. IL-17A plays a central role in the expression of psoriasis signature genes through the induction of IκB-ζ in keratinocytes. Int. Immunol. 2016;28:443-452.

    Not in our library10.1093/intimm/dxw011

  342. 342.

    Salazar Y., Zheng X., Brunn D., Raifer H., Picard F., Zhang Y., Winter H., Guenther S., Weigert A., Weigmann B., et al. Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer. J. Clin. Investig. 2020;130:3560-3575.

    Not in our library10.1172/jci124037

  343. 343.

    Benevides L., da Fonseca D.M., Donate P.B., Tiezzi D.G., De Carvalho D.D., de Andrade J.M., Martins G.A., Silva J.S. IL17 Promotes Mammary Tumor Progression by Changing the Behavior of Tumor Cells and Eliciting Tumorigenic Neutrophils Recruitment. Cancer Res. 2015;75:3788-3799.

    Not in our library10.1158/0008-5472.can-15-0054

  344. 344.

    Huang S., Wei P., Hwang-Verslues W.W., Kuo W., Jeng Y., Hu C., Shew J., Huang C., Chang K., Lee E.Y., et al. TGF-β1 secreted by Tregs in lymph nodes promotes breast cancer malignancy via up-regulation of IL-17RB. EMBO Mol. Med. 2017;9:1660-1680.

    Not in our library10.15252/emmm.201606914

  345. 345.

    Teng M.W.L., Bowman E.P., McElwee J.J., Smyth M.J., Casanova J.-L., Cooper A.M., Cua D.J. IL-12 and IL-23 cytokines: From discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. 2015;21:719-729.

    Not in our library10.1038/nm.3895

  346. 346.

    Langrish C.L., McKenzie B.S., Wilson N.J., de Waal Malefyt R., Kastelein R.A., Cua D.J. IL-12 and IL-23: Master regulators of innate and adaptive immunity. Immunol. Rev. 2004;202:96-105.

    Not in our library10.1111/j.0105-2896.2004.00214.x

  347. 347.

    Gagro A., Servis D., Cepika A.-M., Toellner K.-M., Grafton G., Taylor D.R., Branica S., Gordon J. Type I cytokine profiles of human naive and memory B lymphocytes: A potential for memory cells to impact polarization. Immunology. 2006;118:66-77.

    Not in our library10.1111/j.1365-2567.2006.02342.x

  348. 348.

    Teng M.W.L., Andrews D.M., McLaughlin N., von Scheidt B., Ngiow S.F., Möller A., Hill G.R., Iwakura Y., Oft M., Smyth M.J. IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis. Proc. Natl. Acad. Sci. USA. 2010;107:8328-8333.

    Not in our library10.1073/pnas.1003251107

  349. 349.

    Zhang L., Li J., Li L., Zhang J., Wang X., Yang C., Li Y., Lan F., Lin P. IL-23 selectively promotes the metastasis of colorectal carcinoma cells with impaired Socs3 expression via the STAT5 pathway. Carcinogenesis. 2014;35:1330-1340.

    Not in our library10.1093/carcin/bgu017

  350. 350.

    Sheng S., Zhang J., Ai J., Hao X., Luan R. Aberrant expression of IL-23/IL-23R in patients with breast cancer and its clinical significance. Mol. Med. Rep. 2018;17:4639-4644.

    Not in our library10.3892/mmr.2018.8427

  351. 351.

    D’Elios M.M., Del Prete G., Amedei A. Targeting IL-23 in human diseases. Expert Opin. Ther. Targets. 2010;14:759-774.

    Not in our library10.1517/14728222.2010.497143

  352. 352.
    Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer · 2015
    Corrected
  353. 353.

    Martinenaite E., Munir Ahmad S., Hansen M., Met Ö., Westergaard M.W., Larsen S.K., Klausen T.W., Donia M., Svane I.M., Andersen M.H. CCL22-specific T Cells: Modulating the immunosuppressive tumor microenvironment. OncoImmunology. 2016;5:e1238541.

    Not in our library10.1080/2162402x.2016.1238541

  354. 354.

    Panneerselvam J., Madka V., Rai R., Morris K.T., Houchen C.W., Chandrakesan P., Rao C.V. Inflammatory Mediators and Gut Microbial Toxins Drive Colon Tumorigenesis by IL-23 Dependent Mechanism. Cancers. 2021;13:5159.

    Not in our library10.3390/cancers13205159

  355. 355.

    Chan T.C., Hawkes J.E., Krueger J.G. Interleukin 23 in the skin: Role in psoriasis pathogenesis and selective interleukin 23 blockade as treatment. Ther. Adv. Chronic Dis. 2018;9:111-119.

    Not in our library10.1177/2040622318759282

  356. 356.

    Vignali D.A.A., Kuchroo V.K. IL-12 family cytokines: Immunological playmakers. Nat. Immunol. 2012;13:722-728.

    Not in our library10.1038/ni.2366

  357. 357.

    Almradi A., Hanzel J., Sedano R., Parker C.E., Feagan B.G., Ma C., Jairath V. Clinical Trials of IL-12/IL-23 Inhibitors in Inflammatory Bowel Disease. BioDrugs. 2020;34:713-721.

    Not in our library10.1007/s40259-020-00451-w

  358. 358.

    Zheng H., Ban Y., Wei F., Ma X., Ma X. Regulation of Interleukin-12 Production in Antigen-Presenting Cells. Regulation of Cytokine Gene Expression in Immunity and Diseases. 2016;Volume 941:117-138.

    Not in our library10.1007/978-94-024-0921-5_6

  359. 359.

    Liaskou E., Patel S.R., Webb G., Bagkou Dimakou D., Akiror S., Krishna M., Mells G., Jones D.E., Bowman S.J., Barone F., et al. Increased sensitivity of Treg cells from patients with PBC to low dose IL-12 drives their differentiation into IFN-γ secreting cells. J. Autoimmun. 2018;94:143-155.

    Not in our library10.1016/j.jaut.2018.07.020

  360. 360.

    Zwirner N.W., Ziblat A. Regulation of NK Cell Activation and Effector Functions by the IL-12 Family of Cytokines: The Case of IL-27. Front. Immunol. 2017;8:25.

    Not in our library10.3389/fimmu.2017.00025

  361. 361.

    Oka N., Markova T., Tsuzuki K., Li W., El-Darawish Y., Pencheva-Demireva M., Yamanishi K., Yamanishi H., Sakagami M., Tanaka Y., et al. IL-12 regulates the expansion, phenotype, and function of murine NK cells activated by IL-15 and IL-18. Cancer Immunol. Immunother. 2020;69:1699-1712.

    Not in our library10.1007/s00262-020-02553-4

  362. 362.

    Zhang N., Bevan M.J. CD8+ T Cells: Foot Soldiers of the Immune System. Immunity. 2011;35:161-168.

    Not in our library10.1016/j.immuni.2011.07.010

  363. 363.

    Díaz-Montero C.M., El Naggar S., Al Khami A., El Naggar R., Montero A.J., Cole D.J., Salem M.L. Priming of naive CD8+ T cells in the presence of IL-12 selectively enhances the survival of CD8+CD62Lhi cells and results in superior anti-tumor activity in a tolerogenic murine model. Cancer Immunol. Immunother. 2008;57:563-572.

    Not in our library10.1007/s00262-007-0394-0

  364. 364.

    Zundler S., Neurath M.F. Interleukin-12: Functional activities and implications for disease. Cytokine Growth Factor Rev. 2015;26:559-568.

    Not in our library10.1016/j.cytogfr.2015.07.003

  365. 365.
    Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy · 2019
    No notice
  366. 366.

    Lin Y., Kuang W., Wu B., Xie C., Liu C., Tu Z. IL-12 induces autophagy in human breast cancer cells through AMPK and the PI3K/Akt pathway. Mol. Med. Rep. 2017;16:4113-4118.

    Not in our library10.3892/mmr.2017.7114

  367. 367.

    Lin Z.-W., Wu L.-X., Xie Y., Ou X., Tian P.-K., Liu X.-P., Min J., Wang J., Chen R.-F., Chen Y.-J., et al. The Expression Levels of Transcription Factors T-bet, GATA-3, RORγt and FOXP3 in Peripheral Blood Lymphocyte (PBL) of Patients with Liver Cancer and their Significance. Int. J. Med. Sci. 2015;12:7-16.

    Not in our library10.7150/ijms.8352

  368. 368.
    Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects · 2020
    No notice
  369. 369.

    Tugues S., Burkhard S.H., Ohs I., Vrohlings M., Nussbaum K., vom Berg J., Kulig P., Becher B. New insights into IL-12-mediated tumor suppression. Cell Death Differ. 2015;22:237-246.

    Not in our library10.1038/cdd.2014.134

  370. 370.

    Cao X., Leonard K., Collins L.I., Cai S.F., Mayer J.C., Payton J.E., Walter M.J., Piwnica-Worms D., Schreiber R.D., Ley T.J. Interleukin 12 Stimulates IFN-γ–Mediated Inhibition of Tumor-Induced Regulatory T-Cell Proliferation and Enhances Tumor Clearance. Cancer Res. 2009;69:8700-8709.

    Not in our library10.1158/0008-5472.can-09-1145

  371. 371.
    Differential effects of IL-12 on Tregs and non-Treg T cells: roles of IFN-γ, IL-2 and IL-2R. · 2012
    Not checked
  372. 372.

    El-Shemi A.G., Ashshi A.M., Na Y., Li Y., Basalamah M., Al-Allaf F.A., Oh E., Jung B.-K., Yun C.-O. Combined therapy with oncolytic adenoviruses encoding TRAIL and IL-12 genes markedly suppressed human hepatocellular carcinoma both in vitro and in an orthotopic transplanted mouse model. J. Exp. Clin. Cancer Res. 2016;35:74.

    Not in our library10.1186/s13046-016-0353-8

  373. 373.

    Jia Z., Ragoonanan D., Mahadeo K.M., Gill J., Gorlick R., Shpal E., Li S. IL12 immune therapy clinical trial review: Novel strategies for avoiding CRS-associated cytokines. Front. Immunol. 2022;13:952231.

    Not in our library10.3389/fimmu.2022.952231

  374. 374.
    Localized Interleukin-12 for Cancer Immunotherapy · 2020
    No notice
  375. 375.

    Bekaii-Saab T.S., Roda J.M., Guenterberg K.D., Ramaswamy B., Young D.C., Ferketich A.K., Lamb T.A., Grever M.R., Shapiro C.L., Carson W.E. A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies. Mol. Cancer Ther. 2009;8:2983-2991.

    Not in our library10.1158/1535-7163.mct-09-0820

  376. 376.

    Guo N., Wang W.-Q., Gong X.-J., Gao L., Yang L.-R., Yu W.-N., Shen H.-Y., Wan L.-Q., Jia X.-F., Wang Y.-S., et al. Study of rhIL-12 for treatment of complications after radiotherapy for tumor patients. World J. Clin. Oncol. 2017;8:158.

    Not in our library10.5306/wjco.v8.i2.158

  377. 377.
    The proinflammatory cytokines IL-2, IL-15 and IL-21 modulate the repertoire of mature human natural killer cell receptors · 2007
    No notice
  378. 378.

    Morgan D.A., Ruscetti F.W., Gallo R. Selective in Vitro Growth of T Lymphocytes from Normal Human Bone Marrows. Science. 1976;193:1007-1008.

    Not in our library10.1126/science.181845

  379. 379.

    Raker V.K., Becker C., Landfester K., Steinbrink K. Targeted Activation of T Cells with IL-2-Coupled Nanoparticles. Cells. 2020;9:2063.

    Not in our library10.3390/cells9092063

  380. 380.

    Cosman D. The hematopoietin receptor superfamily. Cytokine. 1993;5:95-106.

    Not in our library10.1016/1043-4666(93)90047-9

  381. 381.

    Rickert M., Wang X., Boulanger M.J., Goriatcheva N., Garcia K.C. The Structure of Interleukin-2 Complexed with Its Alpha Receptor. Science. 2005;308:1477-1480.

    Not in our library10.1126/science.1109745

  382. 382.

    Malek T.R. The Biology of Interleukin-2. Annu. Rev. Immunol. 2008;26:453-479.

    Not in our library10.1146/annurev.immunol.26.021607.090357

  383. 383.

    Wang X., Lupardus P., LaPorte S.L., Garcia K.C. Structural Biology of Shared Cytokine Receptors. Annu. Rev. Immunol. 2009;27:29-60.

    Not in our library10.1146/annurev.immunol.24.021605.090616

  384. 384.

    Gaffen S., Liu K. Overview of interleukin-2 function, production and clinical applications. Cytokine. 2004;28:109-123.

    Not in our library10.1016/j.cyto.2004.06.010

  385. 385.

    Feng Y., Arvey A., Chinen T., van der Veeken J., Gasteiger G., Rudensky A.Y. Control of the Inheritance of Regulatory T Cell Identity by a cis Element in the Foxp3 Locus. Cell. 2014;158:749-763.

    Not in our library10.1016/j.cell.2014.07.031

  386. 386.

    Sim G.C., Radvanyi L. The IL-2 cytokine family in cancer immunotherapy. Cytokine Growth Factor Rev. 2014;25:377-390.

    Not in our library10.1016/j.cytogfr.2014.07.018

  387. 387.

    Kim H.P., Imbert J., Leonard W.J. Both integrated and differential regulation of components of the IL-2/IL-2 receptor system. Cytokine Growth Factor Rev. 2006;17:349-366.

    Not in our library10.1016/j.cytogfr.2006.07.003

  388. 388.

    Bani L. Expression of the IL-2 receptor gamma subunit in resting human CD4 T lymphocytes: mRNA is constitutively transcribed and the protein stored as an intracellular component. Int. Immunol. 1997;9:573-580.

    Not in our library10.1093/intimm/9.4.573

  389. 389.

    Widowati W., Jasaputra D.K., Sumitro S.B., Widodo M.A., Mozef T., Rizal R., Kusuma H.S.W., Laksmitawati D.R., Murti H., Bachtiar I., et al. Effect of interleukins (IL-2, IL-15, IL-18) on receptors activation and cytotoxic activity of natural killer cells in breast cancer cell. Afr. Health Sci. 2020;20:822-832.

    Not in our library10.4314/ahs.v20i2.36

  390. 390.

    Fragelli B.D.D.L., Camillo L., Rodolpho J.M.D.A., de Godoy K.F., de Castro C.A., Brassolatti P., da Silva A.J., Borra R.C., Anibal F.D.F. Antitumor Effect of IL-2 and TRAIL Proteins Expressed by Recombinant Salmonella in Murine Bladder Cancer Cells. Cell. Physiol. Biochem. 2021;55:460-476.

    Not in our library10.33594/000000398

  391. 391.

    Kalia V., Sarkar S., Subramaniam S., Haining W.N., Smith K.A., Ahmed R. Prolonged Interleukin-2Rα Expression on Virus-Specific CD8+ T Cells Favors Terminal-Effector Differentiation In Vivo. Immunity. 2010;32:91-103.

    Not in our library10.1016/j.immuni.2009.11.010

  392. 392.

    Kilinc M.O., Gu T., Harden J.L., Virtuoso L.P., Egilmez N.K. Central Role of Tumor-Associated CD8 + T Effector/Memory Cells in Restoring Systemic Antitumor Immunity. J. Immunol. 2009;182:4217-4225.

    Not in our library10.4049/jimmunol.0802793

  393. 393.

    Liu Y., Zhou N., Zhou L., Wang J., Zhou Y., Zhang T., Fang Y., Deng J., Gao Y., Liang X., et al. IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor. Nat. Immunol. 2021;22:358-369.

    Not in our library10.1038/s41590-020-00850-9

  394. 394.

    Hu X., Ivashkiv L.B. Cross-regulation of Signaling Pathways by Interferon-γ: Implications for Immune Responses and Autoimmune Diseases. Immunity. 2009;31:539-550.

    Not in our library10.1016/j.immuni.2009.09.002

  395. 395.

    Young H.A., Hardy K.J. Role of interferon-γ in immune cell regulation. J. Leukoc. Biol. 1995;58:373-381.

    Not in our library10.1002/jlb.58.4.373

  396. 396.
    Natural killer T cell activation increases iNOS+CD206- M1 macrophage and controls the growth of solid tumor · 2019
    No notice
  397. 397.
    Interferon gamma in cancer immunotherapy · 2018
    No notice
  398. 398.

    Ong C.E.B., Lyons A.B., Woods G.M., Flies A.S. Inducible IFN-γ Expression for MHC-I Upregulation in Devil Facial Tumor Cells. Front. Immunol. 2019;9:3117.

    Not in our library10.3389/fimmu.2018.03117

  399. 399.

    Mendoza J.L., Escalante N.K., Jude K.M., Sotolongo Bellon J., Su L., Horton T.M., Tsutsumi N., Berardinelli S.J., Haltiwanger R.S., Piehler J., et al. Structure of the IFNγ receptor complex guides design of biased agonists. Nature. 2019;567:56-60.

    Not in our library10.1038/s41586-019-0988-7

  400. 400.

    Xu H.-M. Th1 cytokine-based immunotherapy for cancer. Hepatobiliary Pancreat. Dis. Int. 2014;13:482-494.

    Not in our library10.1016/s1499-3872(14)60305-2

  401. 401.

    Tosolini M., Kirilovsky A., Mlecnik B., Fredriksen T., Mauger S., Bindea G., Berger A., Bruneval P., Fridman W.-H., Pagès F., et al. Clinical Impact of Different Classes of Infiltrating T Cytotoxic and Helper Cells (Th1, Th2, Treg, Th17) in Patients with Colorectal Cancer. Cancer Res. 2011;71:1263-1271.

    Not in our library10.1158/0008-5472.can-10-2907

  402. 402.

    Pan J., Zhang M., Wang J., Wang Q., Xia D., Sun W., Zhang L., Yu H., Liu Y., Cao X. Interferon-γ is an autocrine mediator for dendritic cell maturation. Immunol. Lett. 2004;94:141-151.

    Not in our library10.1016/j.imlet.2004.05.003

  403. 403.

    Hosking M.P., Flynn C.T., Whitton J.L. Antigen-Specific Naive CD8 + T Cells Produce a Single Pulse of IFN-γ In Vivo within Hours of Infection, but without Antiviral Effect. J. Immunol. 2014;193:1873-1885.

    Not in our library10.4049/jimmunol.1400348

  404. 404.

    Alspach E., Lussier D.M., Schreiber R.D. Interferon γ and Its Important Roles in Promoting and Inhibiting Spontaneous and Therapeutic Cancer Immunity. Cold Spring Harb. Perspect. Biol. 2019;11:a028480.

    Not in our library10.1101/cshperspect.a028480

  405. 405.

    Kannan Y., Yu J., Raices R.M., Seshadri S., Wei M., Caligiuri M.A., Wewers M.D. IκBζ augments IL-12– and IL-18–mediated IFN-γ production in human NK cells. Blood. 2011;117:2855-2863.

    Not in our library10.1182/blood-2010-07-294702

  406. 406.
    Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion · 2018
    No notice
  407. 407.

    Thiel D., le Du M.-H., Walter R., D’Arcy A., Chène C., Fountoulakis M., Garotta G., Winkler F., Ealick S. Observation of an unexpected third receptor molecule in the crystal structure of human interferon-γ receptor complex. Structure. 2000;8:927-936.

    Not in our library10.1016/s0969-2126(00)00184-2

  408. 408.

    Kotenko S.V., Izotova L.S., Pollack B.P., Mariano T.M., Donnelly R.J., Muthukumaran G., Cook J.R., Garotta G., Silvennoinen O., Ihle J.N., et al. Interaction between the Components of the Interferon γ Receptor Complex. J. Biol. Chem. 1995;270:20915-20921.

    Not in our library10.1074/jbc.270.36.20915

  409. 409.

    Negishi H., Taniguchi T., Yanai H. The Interferon (IFN) Class of Cytokines and the IFN Regulatory Factor (IRF) Transcription Factor Family. Cold Spring Harb. Perspect. Biol. 2018;10:a028423.

    Not in our library10.1101/cshperspect.a028423

  410. 410.
    Human Tumor Antigens and Cancer Immunotherapy · 2015
    No notice
  411. 411.

    Street D., Kaufmann A.M., Vaughan A., Fisher S.G., Hunter M., Schreckenberger C., Potkul R.K., Gissmann L., Qiao L. Interferon-γ Enhances Susceptibility of Cervical Cancer Cells to Lysis by Tumor-Specific Cytotoxic T Cells. Gynecol. Oncol. 1997;65:265-272.

    Not in our library10.1006/gyno.1997.4667

  412. 412.

    Kundu M., Roy A., Pahan K. Selective neutralization of IL-12 p40 monomer induces death in prostate cancer cells via IL-12–IFN-γ. Proc. Natl. Acad. Sci. USA. 2017;114:11482-11487.

    Not in our library10.1073/pnas.1705536114

  413. 413.

    Hao Q., Tang H. Interferon-γ and Smac mimetics synergize to induce apoptosis of lung cancer cells in a TNFα-independent manner. Cancer Cell Int. 2018;18:84.

    Not in our library10.1186/s12935-018-0579-y

  414. 414.

    Song M., Ping Y., Zhang K., Yang L., Li F., Zhang C., Cheng S., Yue D., Maimela N.R., Qu J., et al. Low-Dose IFNγ Induces Tumor Cell Stemness in Tumor Microenvironment of Non–Small Cell Lung Cancer. Cancer Res. 2019;79:3737-3748.

    Not in our library10.1158/0008-5472.can-19-0596

  415. 415.

    Razaghi A., Owens L., Heimann K. Review of the recombinant human interferon gamma as an immunotherapeutic: Impacts of production platforms and glycosylation. J. Biotechnol. 2016;240:48-60.

    Not in our library10.1016/j.jbiotec.2016.10.022

  416. 416.

    Harvat B.L., Seth P., Jetten A.M. The role of p27Kip1 in gamma interferon-mediated growth arrest of mammary epithelial cells and related defects in mammary carcinoma cells. Oncogene. 1997;14:2111-2122.

    Not in our library10.1038/sj.onc.1201055

  417. 417.

    Tau G.Z., Cowan S.N., Weisburg J., Braunstein N.S., Rothman P.B. Regulation of IFN-γ Signaling Is Essential for the Cytotoxic Activity of CD8 + T Cells. J. Immunol. 2001;167:5574-5582.

    Not in our library10.4049/jimmunol.167.10.5574

  418. 418.

    Maimela N.R., Liu S., Zhang Y. Fates of CD8+ T cells in Tumor Microenvironment. Comput. Struct. Biotechnol. J. 2019;17:1-13.

    Not in our library10.1016/j.csbj.2018.11.004

  419. 419.

    Coughlin C.M., Salhany K.E., Gee M.S., LaTemple D.C., Kotenko S., Ma X., Gri G., Wysocka M., Kim J.E., Liu L., et al. Tumor Cell Responses to IFNγ Affect Tumorigenicity and Response to IL-12 Therapy and Antiangiogenesis. Immunity. 1998;9:25-34.

    Not in our library10.1016/s1074-7613(00)80585-3

  420. 420.

    Ibe S., Qin Z., Schüler T., Preiss S., Blankenstein T. Tumor Rejection by Disturbing Tumor Stroma Cell Interactions. J. Exp. Med. 2001;194:1549-1560.

    Not in our library10.1084/jem.194.11.1549

  421. 421.

    Zhang M., Huang L., Ding G., Huang H., Cao G., Sun X., Lou N., Wei Q., Shen T., Xu X., et al. Interferon gamma inhibits CXCL8–CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer. J. Immunother. Cancer. 2020;8:e000308.

    Not in our library10.1136/jitc-2019-000308

  422. 422.
    T Cell Intrinsic USP15 Deficiency Promotes Excessive IFN-γ Production and an Immunosuppressive Tumor Microenvironment in MCA-Induced Fibrosarcoma · 2015
    Not checked
  423. 423.

    Duncan T.J., Rolland P., Deen S., Scott I.V., Liu D.T.Y., Spendlove I., Durrant L.G. Loss of IFNγ Receptor Is an Independent Prognostic Factor in Ovarian Cancer. Clin. Cancer Res. 2007;13:4139-4145.

    Not in our library10.1158/1078-0432.ccr-06-2833

  424. 424.

    Abiko K., Matsumura N., Hamanishi J., Horikawa N., Murakami R., Yamaguchi K., Yoshioka Y., Baba T., Konishi I., Mandai M. IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br. J. Cancer. 2015;112:1501-1509.

    Not in our library10.1038/bjc.2015.101

  425. 425.

    Spranger S., Spaapen R.M., Zha Y., Williams J., Meng Y., Ha T.T., Gajewski T.F. Up-Regulation of PD-L1, IDO, and T regs in the Melanoma Tumor Microenvironment Is Driven by CD8 + T Cells. Sci. Transl. Med. 2013;5:200ra116.

    Not in our library10.1126/scitranslmed.3006504

  426. 426.

    Manguso R.T., Pope H.W., Zimmer M.D., Brown F.D., Yates K.B., Miller B.C., Collins N.B., Bi K., LaFleur M.W., Juneja V.R., et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017;547:413-418.

    Not in our library10.1038/nature23270

  427. 427.

    Patel S.J., Sanjana N.E., Kishton R.J., Eidizadeh A., Vodnala S.K., Cam M., Gartner J.J., Jia L., Steinberg S.M., Yamamoto T.N., et al. Identification of essential genes for cancer immunotherapy. Nature. 2017;548:537-542.

    Not in our library10.1038/nature23477

  428. 428.

    Rooney M.S., Shukla S.A., Wu C.J., Getz G., Hacohen N. Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity. Cell. 2015;160:48-61.

    Not in our library10.1016/j.cell.2014.12.033

  429. 429.

    Grasso C.S., Tsoi J., Onyshchenko M., Abril-Rodriguez G., Ross-Macdonald P., Wind-Rotolo M., Champhekar A., Medina E., Torrejon D.Y., Shin D.S., et al. Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma. Cancer Cell. 2020;38:500-515.e3.

    Not in our library10.1016/j.ccell.2020.08.005

  430. 430.

    Mosser D.M., Zhang X. Interleukin-10: New perspectives on an old cytokine. Immunol. Rev. 2008;226:205-218.

    Not in our library10.1111/j.1600-065x.2008.00706.x

  431. 431.

    Standiford T.J., Deng J.C. INTERLEUKINS IL-10. Encyclopedia of Respiratory Medicine. 2006;373-377.

    Not in our library10.1016/b0-12-370879-6/00480-4

  432. 432.

    Jankovic D., Kullberg M.C., Feng C.G., Goldszmid R.S., Collazo C.M., Wilson M., Wynn T.A., Kamanaka M., Flavell R.A., Sher A. Conventional T-bet+Foxp3− Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 2007;204:273-283.

    Not in our library10.1084/jem.20062175

  433. 433.

    Yoon S., Jones B.C., Logsdon N.J., Harris B.D., Deshpande A., Radaeva S., Halloran B.A., Gao B., Walter M.R. Structure and Mechanism of Receptor Sharing by the IL-10R2 Common Chain. Structure. 2010;18:638-648.

    Not in our library10.1016/j.str.2010.02.009

  434. 434.

    Donnelly R.P., Sheikh F., Kotenko S.V., Dickensheets H. The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain. J. Leukoc. Biol. 2004;76:314-321.

    Not in our library10.1189/jlb.0204117

  435. 435.

    Hamidullah, Changkija B., Konwar R. Role of interleukin-10 in breast cancer. Breast Cancer Res. Treat. 2012;133:11-21.

    Not in our library10.1007/s10549-011-1855-x

  436. 436.

    Schottelius A.J.G., Mayo M.W., Sartor R.B., Baldwin A.S. Interleukin-10 Signaling Blocks Inhibitor of κB Kinase Activity and Nuclear Factor κB DNA Binding. J. Biol. Chem. 1999;274:31868-31874.

    Not in our library10.1074/jbc.274.45.31868

  437. 437.

    Antoniv T.T., Ivashkiv L.B. Interleukin-10-induced gene expression and suppressive function are selectively modulated by the PI3K-Akt-GSK3 pathway: IL-10-induced transcription is modulated by PI3K-Akt-GSK3. Immunology. 2011;132:567-577.

    Not in our library10.1111/j.1365-2567.2010.03402.x

  438. 438.

    Crawley J.B., Williams L.M., Mander T., Brennan F.M., Foxwell B.M.J. Interleukin-10 Stimulation of Phosphatidylinositol 3-Kinase and p70 S6 Kinase Is Required for the Proliferative but Not the Antiinflammatory Effects of the Cytokine. J. Biol. Chem. 1996;271:16357-16362.

    Not in our library10.1074/jbc.271.27.16357

  439. 439.

    Wang T., Ge Y., Xiao M., Lopez-Coral A., Azuma R., Somasundaram R., Zhang G., Wei Z., Xu X., Rauscher F.J., et al. Melanoma-derived conditioned media efficiently induce the differentiation of monocytes to macrophages that display a highly invasive gene signature: Melanoma-conditioned media induce monocytes to Mφ. Pigment Cell Melanoma Res. 2012;25:493-505.

    Not in our library10.1111/j.1755-148x.2012.01005.x

  440. 440.

    McGeachy M.J., Bak-Jensen K.S., Chen Y., Tato C.M., Blumenschein W., McClanahan T., Cua D.J. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology. Nat. Immunol. 2007;8:1390-1397.

    Not in our library10.1038/ni1539

  441. 441.

    Jiang X. Macrophage-produced IL-10 limits the chemotherapy efficacy in breast cancer. J. Zhejiang Univ.-Sci. B. 2015;16:44-45.

    Not in our library10.1631/jzus.b1400352

  442. 442.

    Yang C., He L., He P., Liu Y., Wang W., He Y., Du Y., Gao F. Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10/STAT3/bcl-2 signaling pathway. Med. Oncol. 2015;32:14.

    Not in our library10.1007/s12032-014-0352-6

  443. 443.

    Naing A., Wong D.J., Infante J.R., Korn W.M., Aljumaily R., Papadopoulos K.P., Autio K.A., Pant S., Bauer T.M., Drakaki A., et al. Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): A multicentre, multicohort, open-label, phase 1b trial. Lancet Oncol. 2019;20:1544-1555.

    Not in our library10.1016/s1470-2045(19)30514-5

  444. 444.

    Naing A., Papadopoulos K.P., Autio K.A., Ott P.A., Patel M.R., Wong D.J., Falchook G.S., Pant S., Whiteside M., Rasco D.R., et al. Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors. J. Clin. Oncol. 2016;34:3562-3569.

    Not in our library10.1200/jco.2016.68.1106

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